药学学报

Mechanism of action	Drugs that targets the nuclear bodies	Class of compounds	Cancer type
Topoisomerase Ⅰ inhibition	Topotecan	Camptothecins	Ovarian cancer, small cell lung cancer, or cervical cancer
Irinotecan	Camptothecins	Metastatic carcinoma of the colon or rectum and pancreatic adenocarcinoma
Topoisomerase Ⅱ inhibition	Etoposide	Epipodophyllotoxins	Sarcoma, glioblastoma, lung, testicular, haematological cancers
Teniposide	Epipodophyllotoxins	Refractory childhood acute lymphoblastic leukemia
Mitoxantrone	Anthraquinone	Acute myeloid leukemia, hepatocellular carcinoma, breast cancer
Amsacrine	Acridine	Tumor
Doxorubicin	Anthracycline	Haematological cancers, bladder, breast, stomach, lung, ovarian and thyroid cancer, sarcoma
Idarubicin	Anthracycline	Acute myeloid leukemia
DNA intercalating agent	Daunorubicin	Anthracycline	Nonlymphocytic leukemia and acute lymphocytic leukemia
Actinomycin D	Antibiotic	Wilms' tumour, sarcoma
rDNA crosslinking agent	Cisplatin/oxaliplatin	Platinum compound	Sarcoma, lymphoma, carcinoma
Mitomycin C	Antibiotic	Stomach or pancreatic adenocarcinoma; anal, bladder, breast, cervical, colorectal, head, non-small-cell lung cancer
Disrupting nucleolar integrity	Roscovitine/olomoucine DRB	CDK inhibitors	Adenocarcinoma, B-cell malignancies, breast cancer
Inhibiting RNA Pol I activity	Quinacrine	Selective inhibitor of RNA Pol I	Acute myeloid leukemia
CX-5461	Selective inhibitor of RNA Pol I	Haematological cancers
9-Hydroxyellipticine (9HE)	Selective inhibitor of RNA Pol I	Breast cancer
Thymidylate synthase/rRNA/rDNA synthesis inhibitor	5-Fluorouracil	Pyrimidine nucleotide analogue	Colon, rectum, head, neck cancers
Inhibiting mTOR signalling resulting in inhibition of ribosome biogenesis	Everolimus	mTOR signalling inhibitor	Renal cell carcinoma, breast cancer and lymphoma
Inhibiting AKT signalling resulting in suppression of rDNA gene transcription	AKTi-1/2/MK-2206	AKT signalling inhibitor	Non-small-cell lung cancer
Inhibiting the MDM2-P53 interaction	JNJ-26854165	Tryptamine derivative	Solid tumours
AMG 232	Piperidinone derivative	Breast cance
Forced degradation of PML/RARα and induction of PML nucleosome assembly	ATO and ATRA	Arsenic compound and vitamin A acid	Acute promyelocytic leukemia
Double targeting mitochondria cooperatively clears acute myeloid leukemia and prolongs survival by targeting PML	Venetoclax and actinomycin D	Selective inhibitor of BCL2 and antibiotic	Acute myeloid leukemia
Target mitochondria, release mtDNA, activate cGAS signal pathway and promote ROS production, restore PML nucleosome formation	Actinomycin D	Antibiotic	Acute myeloid leukemia with recurrent/refractory NPM1 mutation

Mechanism of action

Drugs that targets the nuclear bodies

Class of compounds

Cancer type

Topoisomerase Ⅰ inhibition

Topotecan

Camptothecins

Ovarian cancer, small cell lung cancer, or cervical cancer

Irinotecan

Camptothecins

Metastatic carcinoma of the colon or rectum and pancreatic adenocarcinoma

Topoisomerase Ⅱ inhibition

Etoposide

Epipodophyllotoxins

Sarcoma, glioblastoma, lung, testicular, haematological cancers

Teniposide

Epipodophyllotoxins

Refractory childhood acute lymphoblastic leukemia

Mitoxantrone

Anthraquinone

Acute myeloid leukemia, hepatocellular carcinoma, breast cancer

Amsacrine

Acridine

Tumor

Doxorubicin

Anthracycline

Haematological cancers, bladder, breast, stomach, lung, ovarian and thyroid cancer, sarcoma

Idarubicin

Anthracycline

Acute myeloid leukemia

DNA intercalating agent

Daunorubicin

Anthracycline

Nonlymphocytic leukemia and acute lymphocytic leukemia

Actinomycin D

Antibiotic

Wilms' tumour, sarcoma

rDNA crosslinking agent

Cisplatin/oxaliplatin

Platinum compound

Sarcoma, lymphoma, carcinoma

Mitomycin C

Antibiotic

Stomach or pancreatic adenocarcinoma; anal, bladder, breast, cervical, colorectal, head, non-small-cell lung cancer

Disrupting nucleolar integrity

Roscovitine/olomoucine DRB

CDK inhibitors

Adenocarcinoma, B-cell malignancies, breast cancer

Inhibiting RNA Pol I activity

Quinacrine

Selective inhibitor of RNA Pol I

Acute myeloid leukemia

CX-5461

Selective inhibitor of RNA Pol I

Haematological cancers

9-Hydroxyellipticine (9HE)

Selective inhibitor of RNA Pol I

Breast cancer

Thymidylate synthase/rRNA/rDNA synthesis inhibitor

5-Fluorouracil

Pyrimidine nucleotide analogue

Colon, rectum, head, neck cancers

Inhibiting mTOR signalling resulting in inhibition of ribosome biogenesis

Everolimus

mTOR signalling inhibitor

Renal cell carcinoma, breast cancer and lymphoma

Inhibiting AKT signalling resulting in suppression of rDNA gene transcription

AKTi-1/2/MK-2206

AKT signalling inhibitor

Non-small-cell lung cancer

Inhibiting the MDM2-P53 interaction

JNJ-26854165

Tryptamine derivative

Solid tumours

AMG 232

Piperidinone derivative

Breast cance

Forced degradation of PML/RARα and induction of PML nucleosome assembly

ATO and ATRA

Arsenic compound and vitamin A acid

Acute promyelocytic leukemia

Double targeting mitochondria cooperatively clears acute myeloid leukemia and prolongs survival by targeting PML

Venetoclax and actinomycin D

Selective inhibitor of BCL2 and antibiotic

Acute myeloid leukemia

Target mitochondria, release mtDNA, activate cGAS signal pathway and promote ROS production, restore PML nucleosome formation

Actinomycin D

Antibiotic

Acute myeloid leukemia with recurrent/refractory NPM1 mutation

Mechanism of action	Drugs that targets the nuclear bodies	Class of compounds	Cancer type
Topoisomerase Ⅰ inhibition	Topotecan	Camptothecins	Ovarian cancer, small cell lung cancer, or cervical cancer
Irinotecan	Camptothecins	Metastatic carcinoma of the colon or rectum and pancreatic adenocarcinoma
Topoisomerase Ⅱ inhibition	Etoposide	Epipodophyllotoxins	Sarcoma, glioblastoma, lung, testicular, haematological cancers
Teniposide	Epipodophyllotoxins	Refractory childhood acute lymphoblastic leukemia
Mitoxantrone	Anthraquinone	Acute myeloid leukemia, hepatocellular carcinoma, breast cancer
Amsacrine	Acridine	Tumor
Doxorubicin	Anthracycline	Haematological cancers, bladder, breast, stomach, lung, ovarian and thyroid cancer, sarcoma
Idarubicin	Anthracycline	Acute myeloid leukemia
DNA intercalating agent	Daunorubicin	Anthracycline	Nonlymphocytic leukemia and acute lymphocytic leukemia
Actinomycin D	Antibiotic	Wilms' tumour, sarcoma
rDNA crosslinking agent	Cisplatin/oxaliplatin	Platinum compound	Sarcoma, lymphoma, carcinoma
Mitomycin C	Antibiotic	Stomach or pancreatic adenocarcinoma; anal, bladder, breast, cervical, colorectal, head, non-small-cell lung cancer
Disrupting nucleolar integrity	Roscovitine/olomoucine DRB	CDK inhibitors	Adenocarcinoma, B-cell malignancies, breast cancer
Inhibiting RNA Pol I activity	Quinacrine	Selective inhibitor of RNA Pol I	Acute myeloid leukemia
CX-5461	Selective inhibitor of RNA Pol I	Haematological cancers
9-Hydroxyellipticine (9HE)	Selective inhibitor of RNA Pol I	Breast cancer
Thymidylate synthase/rRNA/rDNA synthesis inhibitor	5-Fluorouracil	Pyrimidine nucleotide analogue	Colon, rectum, head, neck cancers
Inhibiting mTOR signalling resulting in inhibition of ribosome biogenesis	Everolimus	mTOR signalling inhibitor	Renal cell carcinoma, breast cancer and lymphoma
Inhibiting AKT signalling resulting in suppression of rDNA gene transcription	AKTi-1/2/MK-2206	AKT signalling inhibitor	Non-small-cell lung cancer
Inhibiting the MDM2-P53 interaction	JNJ-26854165	Tryptamine derivative	Solid tumours
AMG 232	Piperidinone derivative	Breast cance
Forced degradation of PML/RARα and induction of PML nucleosome assembly	ATO and ATRA	Arsenic compound and vitamin A acid	Acute promyelocytic leukemia
Double targeting mitochondria cooperatively clears acute myeloid leukemia and prolongs survival by targeting PML	Venetoclax and actinomycin D	Selective inhibitor of BCL2 and antibiotic	Acute myeloid leukemia
Target mitochondria, release mtDNA, activate cGAS signal pathway and promote ROS production, restore PML nucleosome formation	Actinomycin D	Antibiotic	Acute myeloid leukemia with recurrent/refractory NPM1 mutation

Mechanism of action

Drugs that targets the nuclear bodies

Class of compounds

Cancer type

Topoisomerase Ⅰ inhibition

Topotecan

Camptothecins

Ovarian cancer, small cell lung cancer, or cervical cancer

Irinotecan

Camptothecins

Metastatic carcinoma of the colon or rectum and pancreatic adenocarcinoma

Topoisomerase Ⅱ inhibition

Etoposide

Epipodophyllotoxins

Sarcoma, glioblastoma, lung, testicular, haematological cancers

Teniposide

Epipodophyllotoxins

Refractory childhood acute lymphoblastic leukemia

Mitoxantrone

Anthraquinone

Acute myeloid leukemia, hepatocellular carcinoma, breast cancer

Amsacrine

Acridine

Tumor

Doxorubicin

Anthracycline

Haematological cancers, bladder, breast, stomach, lung, ovarian and thyroid cancer, sarcoma

Idarubicin

Anthracycline

Acute myeloid leukemia

DNA intercalating agent

Daunorubicin

Anthracycline

Nonlymphocytic leukemia and acute lymphocytic leukemia

Actinomycin D

Antibiotic

Wilms' tumour, sarcoma

rDNA crosslinking agent

Cisplatin/oxaliplatin

Platinum compound

Sarcoma, lymphoma, carcinoma

Mitomycin C

Antibiotic

Stomach or pancreatic adenocarcinoma; anal, bladder, breast, cervical, colorectal, head, non-small-cell lung cancer

Disrupting nucleolar integrity

Roscovitine/olomoucine DRB

CDK inhibitors

Adenocarcinoma, B-cell malignancies, breast cancer

Inhibiting RNA Pol I activity

Quinacrine

Selective inhibitor of RNA Pol I

Acute myeloid leukemia

CX-5461

Selective inhibitor of RNA Pol I

Haematological cancers

9-Hydroxyellipticine (9HE)

Selective inhibitor of RNA Pol I

Breast cancer

Thymidylate synthase/rRNA/rDNA synthesis inhibitor

5-Fluorouracil

Pyrimidine nucleotide analogue

Colon, rectum, head, neck cancers

Inhibiting mTOR signalling resulting in inhibition of ribosome biogenesis

Everolimus

mTOR signalling inhibitor

Renal cell carcinoma, breast cancer and lymphoma

Inhibiting AKT signalling resulting in suppression of rDNA gene transcription

AKTi-1/2/MK-2206

AKT signalling inhibitor

Non-small-cell lung cancer

Inhibiting the MDM2-P53 interaction

JNJ-26854165

Tryptamine derivative

Solid tumours

AMG 232

Piperidinone derivative

Breast cance

Forced degradation of PML/RARα and induction of PML nucleosome assembly

ATO and ATRA

Arsenic compound and vitamin A acid

Acute promyelocytic leukemia

Double targeting mitochondria cooperatively clears acute myeloid leukemia and prolongs survival by targeting PML

Venetoclax and actinomycin D

Selective inhibitor of BCL2 and antibiotic

Acute myeloid leukemia

Target mitochondria, release mtDNA, activate cGAS signal pathway and promote ROS production, restore PML nucleosome formation

Actinomycin D

Antibiotic

Acute myeloid leukemia with recurrent/refractory NPM1 mutation

核体在肿瘤中的研究进展

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刘清远 , 刘蕴瑶 ^* , 许义婷 , 许宇饺 , 强磊 ^*

药学学报 | 综述 2024,59(12): 3179-3188

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药学学报 | 综述 2024, 59(12): 3179-3188

核体在肿瘤中的研究进展

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刘清远, 刘蕴瑶^*, 许义婷, 许宇饺, 强磊^*

作者信息

中国药科大学基础医学与临床药学学院, 江苏南京 210000

通讯作者:

^*刘蕴瑶, Tel: 15150686765, E-mail: 15150686765@163.com;

强磊, Tel: 86-25-86185641, E-mail: lqiang@cpu.edu.cn

Research progress of nuclear bodies in tumor

Qing-yuan LIU, Yun-yao LIU^*, Yi-ting XU, Yu-jiao XU, Lei QIANG^*

Affiliations

School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210000, China

出版时间: 2024-12-12 doi: 10.16438/j.0513-4870.2024-0597

文章导航

摘要

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哺乳动物细胞核是高度结构化的, 并组织成称为核体的各种无膜核隔室。核体是高度动态的结构, 内部聚集着多种物质以促进某些生物反应更加高效地进行, 在肿瘤发生、细胞凋亡、抗病毒防御等不同生物学过程和应激条件下动态地产生应答, 在调控细胞稳态方面发挥重要的作用。肿瘤作为公共健康的重大问题, 寻找新的可用靶点是肿瘤治疗的关键。核体如何参与肿瘤的发生还鲜有报道。本综述以期为核体如何调控肿瘤进展提供新的认识, 并为肿瘤的防治提供新的有效策略。

关键词

核体 / 核仁 / 早幼粒细胞白血病核体 / 核散斑体 / 旁斑 / 肿瘤

Abstract

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The mammalian cell nucleus is highly structured and organized into various membrane-less nuclear compartments called nuclear bodies. Nuclear bodies are highly dynamic structures, with a variety of substances gathered inside to promote the more efficient conduct of certain biological reactions. It dynamically produces responses under different biological processes and stress conditions such as tumorigenesis, apoptosis, antiviral defense, and plays an important role in regulating cell homeostasis. Tumor is a major public health problem, and finding new targets is the key to tumor therapy. How the nuclear bodies are involved in the development of tumor has not been reported. This review aims to provide a new understanding of how the nuclear bodies regulates tumor progression and provide a new effective strategy for tumor prevention and treatment.

Key words

nuclear body / nucleolus / promyelocytic leukemia nuclear body / nuclear speckle / paraspeckle / tumor

引用本文

刘清远, 刘蕴瑶, 许义婷, 许宇饺, 强磊. 核体在肿瘤中的研究进展. 药学学报, 2024 , 59 (12) : 3179 -3188 . DOI: 10.16438/j.0513-4870.2024-0597

Qing-yuan LIU, Yun-yao LIU, Yi-ting XU, Yu-jiao XU, Lei QIANG. Research progress of nuclear bodies in tumor[J]. Acta Pharmaceutica Sinica, 2024 , 59 (12) : 3179 -3188 . DOI: 10.16438/j.0513-4870.2024-0597

正文

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细胞核中包含无数离散的亚细胞器, 称为核体。核体是参与各种细胞过程并对细胞核中的细胞刺激作出反应的生物分子凝聚物^[1], 是细胞核重要的组成部分。与传统的细胞质细胞器相似, 核体分隔了核空间, 在核内创造了具有独特功能的环境^[2], 从而募集反应物和底物, 潜在地促进更有效的生物反应^[3]。核体以从圆球到不规则形状的各种形式出现^[4], 包括核仁(nucleolus)、早幼粒细胞白血病(promyelocytic leukemia, PML) 核体、核散斑体(nuclear speckle)、核应激小体(nuclear stress body)、旁斑(paraspeckle)、卡哈尔体(Cajal body)、多梳小体(polycomb body) 等^[5]。这些富含蛋白质和RNA的无膜小体, 动态响应基本生理过程以及各种形式的应激、代谢条件和细胞信号传导的改变^[6], 在涉及稳态、分化、发育和疾病的基本细胞过程中发挥重要作用^[7]。

核体被认为是基因组的多功能伴侣, 作为一个高度动态的结构, 核体组分可以与周围的核质快速交换, 并且其结构完整性由瞬时的蛋白质-蛋白质和可能的蛋白质-RNA相互作用介导。一些核体的形成是参与基因表达和基因组维护的结果^[8]。空间多组学的最新进展揭示了核体和染色质之间错综复杂的相互作用^[9], 从核体组分和相邻DNA之间的直接相互作用^[8]到核体与基因组结构和功能之间的多维动态^[10]。Shan等^[1]提出核体充当“组装器”和“枢纽”来调节染色质组织和基因表达, 响应于细胞应激。基于核体的重要生物学功能, 核体的结构与功能异常被证明与肿瘤发生发展相关。在肿瘤细胞中已经观察到许多核体结构与功能的改变, 包括核仁数量和大小的变化、PML核体的破坏、核斑点形态学改变等。这些改变可以是某些肿瘤类型和阶段性的特征, 并且还可能与肿瘤细胞改变的功能特性有关^[11]。因此, 能否利用肿瘤细胞中核体结构的差异进行诊断和开发新的抗癌药物值得思考, 增加对核体的理解可能为抗肿瘤药物的研发提供新方向。鉴于部分核体在肿瘤中的研究较少, 可用信息相对有限。因此本文重点对核仁、PML核体、核散斑体、旁斑4种核体在肿瘤中的研究进展展开综述。

1 核仁

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核仁是细胞核内最明显的结构, 是一种动态的、非膜结合的隔室, 包含核糖体DNA (ribosomal DNA, rDNA) 簇及其转录物(ribosomal RNA, rRNA), 以及参与核仁内外许多核功能的数百种蛋白质^{[12, 13]}。核仁的主要功能是合成和加工rRNA和核糖体组装^[14]。在该过程中, 核糖体所有成分在核仁中合成、修饰、组装, 最后被携带到细胞质中, 形成成熟的核糖体^[14]。核仁结构和功能的完整性是保证核糖体生物正常发生所必需的^[12]。已有多种基因组学和蛋白质组学研究表明核仁的功能不仅限于核糖体生物合成, 其在调节多种细胞核和细胞过程中起到中心枢纽的作用^[15], 如参与基因组的维持、修复和稳定性、细胞周期的调控、细胞衰老、应激反应、端粒维持和核结构等^[16]。

与核仁的多功能性相一致, 核仁功能障碍与多种疾病相关联, 如癌症、神经疾病(帕金森病和亨廷顿舞蹈病)、心血管疾病(缺血、心力衰竭、心肌梗死和心肌细胞肥大)、衰老等^{[17, 18]}。核仁是一种有效的疾病生物标志物和癌症治疗的靶点, 核仁大小和数量、核仁内蛋白的改变以及核糖体生物合成的异常都与癌症的发生发展相关。

核仁大小或数量增加被视为是几种肿瘤预后不良的临床相关标志^[19]。据报道, 正常前列腺细胞核仁数量为1.76个, 而前列腺癌细胞有2.65~3.12个核仁^[20]; 良性乳腺肿瘤细胞有2.96个核仁, 恶性肿瘤有4.0个核仁^{[20, 21]}。有研究表明肿瘤中的β-晶状体蛋白B2 (β-crystallin B2, CRYβB2) 促进去分化、间质标记物和癌症相关成纤维细胞的增加以及核仁的增大, 且CRYβB2通过上调三阴性乳腺癌中的核仁素促进肿瘤发生^[22]。

核仁内存在大量核仁蛋白(nucleolar proteins, NOPs) 和核糖体蛋白(ribosomal proteins, RPs), 其表达改变与肿瘤的发生发展有关。在多类肿瘤中经常出现核糖体蛋白表达的改变^[19]。如单个核糖体蛋白的过度表达与多种癌症的不良预后相关: 卵巢癌中的核糖体蛋白侧茎亚基P0、P1、P2 (ribosomal protein lateral stalk subunit P0、P1、P2, RPLP0、RPLP1和RPLP2)^[23]以及胶质母细胞瘤中的RPS11和RPS20^[24]。并且, RPL15或RPL35的过表达足以增加乳腺癌小鼠模型中的转移负荷^[25]。此外, 已在肿瘤样品中检测到编码核糖体蛋白的基因改变, 表明它们作为致癌基因或肿瘤抑制因子的作用。如在黑素瘤和T细胞急性淋巴细胞白血病中观察到RPL11的突变, 而在T细胞急性淋巴细胞白血病和多发性骨髓瘤、黑素瘤、胶质母细胞瘤和乳腺癌中发生RPL5的缺失或失活突变^[15]。

核仁中最丰富的蛋白质核仁素在几种类型的肿瘤中被发现过表达, 如黑色素瘤、白血病、胃癌、神经胶质瘤、结直肠癌、肝细胞癌、室管膜瘤、肺癌和乳腺癌。其中一些研究认为, 较高水平的核仁素与白血病、神经胶质瘤、肝细胞癌和乳腺肿瘤的预后不良呈正相关^[26]。有实验证明核仁蛋白NOP10高表达是乳腺癌预后不良的生物标志物, 其表达有助于预测化疗耐药性^[27]。据Ma等^[28]报道, NOP2在各种癌症类型中高度表达, 并且它可以促进小鼠成纤维细胞生长以及肿瘤形成, 影响细胞周期, 刺激细胞增殖, 增加核仁活性, 并与体内和体外癌症侵袭性相关。也有研究表明NOP2可以作为透明细胞肾细胞癌总体生存率的潜在预后预测因子^[29]。

除了可导致癌症发展倾向的核糖体蛋白和核仁蛋白质的改变之外, 在癌症中观察到rDNA拷贝数的改变。癌症中最常见的rDNA拷贝数改变是5S rDNA重复序列的扩增和45S rDNA的减少或丢失^{[30, 31]}。作为rRNA前体转录的主要作用因子, 核仁驻留RNA聚合酶I (RNA polymerase I, RNA Pol I) 的活性在癌症中经常升高, 并且RNA Pol I过度激活与几种肿瘤的不良预后相关, 抑制RNA Pol I转录成为癌症治疗的有效方法^[32]。

目前靶向核仁的肿瘤治疗药物, 主要包括以下几大类: 第一类是直接或间接靶向细胞核结构或功能的化合物, 这些化合物属于主要通过破坏核仁完整性起作用的试剂, 如rDNA嵌入剂、烷基化交联剂或干扰rDNA转录和成熟; 第二类核仁靶向药物是核糖体生物合成抑制剂(RNA Pol I直接抑制剂), 如小分子氟喹诺酮衍生物CX-3543 (也称为quarfloxin); 第三类是靶向调节核糖体分子信号通路的化合物。由Myc、Ras/ERK、mTOR和Akt/PKB介导的致癌信号传导和由p53、Rb、ARF和PTEN改变介导的肿瘤抑制途径将其信号会聚到核仁, 调控重要的生理过程。如Akt抑制剂(AKTi-1/2和MK-2206) 显示出显著的抗肿瘤功效。体外和体内模型实验表明, 它们的活性通过抑制rDNA转录和诱导细胞凋亡介导^[19]。

除此之外, 不容忽视的是核仁参与多种肿瘤相关信号通路的调控, 核仁应激更是引起人们的关注。核仁应激已被公认为通过启动各种与应激相关的信号通路而在应激反应中发挥不可或缺的作用。且在核仁应激过程中, 核仁蛋白在核仁和核质之间穿梭。因此, 能否通过对核仁应激的干预来治疗肿瘤需要进一步研究。

2 PML核体

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PML核体在核质中检测为离散的大分子灶, 很少在细胞质中检测到。在哺乳动物的细胞核中通常存在1~10个直径为0.2~1.0 µm的PML核体。PML核体的数量、大小和形态是动态的, 并根据细胞类型、细胞周期阶段以及生理和病理刺激(特别是细胞应激信号) 而变化^[33]。与其他核体(如核仁和核应激颗粒, 其中含有核酸, 特别是RNA) 相比, PML核体是否包含核酸仍存在争议。但很明显, 它们由多种不同的蛋白质组成, 是多蛋白复合物^[34]。肿瘤抑制因子PML蛋白是PML核体的主要组织者, 除此之外, 已报告超过170种蛋白质组成型或瞬时存在于PML核体中, 斑点蛋白100 (speckled protein 100, Sp100) 是定位于这些核体中的第一个特征性蛋白质^{[11, 34, 35]}。

PML核体已被证明参与许多细胞过程, 包括蛋白质修饰, 特别是蛋白质SUMO化、基因表达和表观遗传调控、DNA损伤反应、细胞凋亡、细胞衰老和抗病毒反应。此外, PML核体通过充当蛋白质的储存库与调节核蛋白的可用性相关。在特定刺激下, 如热休克、细胞因子信号传导或遗传毒性应激, 蛋白质可从PML核体中释放从而发挥作用。最后, PML核体还通过募集SUMO靶向的E3泛素连接酶和调节细胞质应激颗粒的分解在蛋白质降解和蛋白质质量控制中发挥作用, 在细胞核和细胞质应激反应途径之间充当分子接头^{[34, 36-38]}。

PML核体在肿瘤中已经得到了广泛的研究, 特别是在急性髓细胞白血病(acute myeloid leukemia, AML) 和急性早幼粒细胞白血病(acute promyelocytic leukemia, APL) 中^[39]。超过90%的APL患者中存在染色体易位, 该易位将PML基因与编码维甲酸受体α (retinoic acid receptor α, RARα) 的基因结合。产生的PML/RARα致癌融合蛋白破坏PML核体的结构完整性, 使其离域成无数微小斑点, 并干扰核受体信号传导, 从而抑制这些患者的细胞分化并驱动白血病致癌^{[34, 40]}。目前临床上治疗APL采用的是三氧化二砷(ATO) 和全反式维甲酸(all-trans retinoic acid, ATRA) 联合治疗^[41]。从机制上讲, ATRA通过与PML/RARα的RARα部分相互作用促进PML/RARα降解, 砷靶向PML和PML/RARα的PML部分。类金属不仅可以强制PML/RARα降解, 而且通过靶向非重排等位基因表达的PML蛋白来触发快速的PML核体组装。这两种效应共同逆转癌细胞PML核体的变化, 诱导PML核体重组, 导致p53激活、p53依赖性衰老程序和白血病起始细胞的根除, 使得超过95%的APL患者得到缓解^{[34, 42, 43]}。

PML核体是可药物化的, 干扰素(interferon, IFN) 和砷联合靶向将有效协同地诱导核体形成、PML募集伴侣蛋白并将其类小泛素化, 随后降解, 消除不需要的蛋白质^[44]。如TAX病毒癌蛋白驱动成人T细胞白血病/淋巴瘤, IFN/ATO组合驱动这些白血病细胞系中的细胞凋亡, 清除小鼠模型中的疾病, 并且在患者中具有一些临床功效^[44]。Rérolle等^{[45, 46]}也提出PML核体可以通过干扰素或ATO以外的其他化合物进行微调, 包括专门促进或阻碍PML核体生物合成的药物, PML核体已知的调节剂可能具有比最初想象的更广泛的临床用途。

PML是一种促进细胞凋亡或衰老的抑癌基因, p53是细胞周期的关键调节蛋白。有研究表明, PML是Ras诱导的p53介导的衰老的重要参与者。在多种情况下, p53的激活需要PML。且p53及许多调节酶可以在PML核体中检测到, 这表明PML核体浓缩p53调节因子以实现翻译后修饰(磷酸化、类小泛素化、乙酰化等)。特定PML形式的过度表达导致p53的稳定和激活, 最终在没有任何其他信号的情况下触发过早衰老^[44]。PML缺失与前列腺癌、结肠癌、乳腺癌和肺癌的进展有关, 而低水平的PML与预后不良相关^[39]。在肝癌的治疗中, PML表达水平增加会延长肝癌切除后的生存期, 降低肝癌的复发率, 但PML的高表达会抑制ATO在肝癌细胞中的抗肿瘤作用^[47]。此外, PML能够通过调控线粒体代谢, 增强人卵巢癌的化疗敏感性^[48], PML的失活还能促进前列腺癌的发展^[49], 癌蛋白WDR4 (WD repeat domain 4) 可以通过泛素化对PML进行负调节, 经过泛素化的PML可以激活相关的下游基因, 通过促进免疫抑制和转移前肿瘤微环境来促进肺癌的进展^[50]。

但一些研究也揭示了PML通过控制干性和代谢重组而促进肿瘤的作用。在慢性髓性白血病中, PML促进造血细胞的干细胞性, 有利于维持白血病起始细胞^[51]。类似的, 在实体瘤中, PML会刺激癌细胞的代谢燃料(脂质、ATP), PML高表达还能通过转录调控缺氧诱导因子靶基因来促进三阴性乳腺癌细胞的迁移、侵袭和转移, 通过抑制PML的表达也能抑制三阴性乳腺癌的发展^[52]。PML与SRY盒转录因子9 (SRY-box transcription factor 9, SOX9, 一种与脑胶质瘤相关的转录因子) 启动子结合, 直接调控胶质母细胞瘤细胞中SOX9的转录, 以维持胶质母细胞瘤细胞的活性^[53]。PML也可以通过抑制Slit引导配体1 (slit guidance ligand 1, SLIT1, 进化保守的具有趋化活性的糖蛋白家族成员) 促进细胞的迁移^[54]。

总结来说, PML在人类癌症中扮演着双重角色, 这提示在白血病和实体瘤的治疗中, PML可以作为一个潜在的靶点。砷剂靶向治疗也许可以拓展到AML、慢性粒细胞白血病(chronic myeloid leukemia, CML) 等其他类型白血病和乳腺癌、胶质瘤等实体肿瘤的治疗中, 从而建立以PML核体为核心的靶向治疗新策略。

3 核散斑体

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核散斑体是位于细胞核内的、小的、无膜的细胞器, 也称为“染色质间颗粒簇”。在间期, 细胞核中含有20~50个直径可达几微米的核斑点, 每个斑点由许多小颗粒组成, 由细纤维连接。核散斑体的大小和数量随不同的细胞类型而变化, 也被各种类型的细胞应激所诱导^[55]。核散斑体由RNA和各种RNA代谢调节蛋白组成, 含有很少或不含DNA。核散斑体中超过50%的蛋白质参与转录或剪接调控, 包括斑点核心蛋白、转录调节分子、RNA结合蛋白和snRNP等。核散斑体作为协调复杂RNA代谢的调节中心, 调控基因转录、前体mRNA剪接、RNA修饰和mRNA核输出过程^[1]; 还可以与一些转录因子, 如p53协同作用, 增强某些基因的表达, 从而发挥肿瘤抑制的作用^[55]。

一些罕见的疾病是由核散斑体中发现的编码蛋白质和非编码RNA的基因突变直接引起的。如色素性视网膜炎, 其由PRPF8、PRPF3、SNRNP200和PRPF6基因突变引起; 下颌骨面骨发育不全(Guion-Almeida型) 由EFTUD2基因突变引起; 以及桡骨缺失综合征由RBM8A基因突变引起。大多数与核散斑体功能障碍相关的疾病, 包括癌症和病毒性疾病, 都与这些结构间接相关^[56]。

核散斑体作为剪接因子储存和修饰的位点, 参与剪接调控。而致癌作用与选择性剪接畸变密切相关。选择性剪接是一种关键的转录后调控机制, 被95%以上的人类基因使用, 它使单个基因能够产生不同的RNA同种型来促进蛋白质组学和功能多样性。在过去十几年中, 全基因转录组测序研究表明, 选择性剪接在组胚和发育阶段以特异性方式受到严格调控, 但在多种癌症类型中经常失调^[57]。选择性剪接畸变是由参与选择性剪接的蛋白质表达改变引起的, 通常导致核斑点形态学紊乱^[56]。在许多类型的癌症中都观察到核散斑体形成蛋白[包括富含丝氨酸/精氨酸蛋白(serine/arginine-rich protein, SRSFs)] 的过表达。异常高水平的SRSF1已被证明足以诱导肿瘤发生^[58], SRSF3在肿瘤细胞增殖、迁移和侵袭中起重要作用, 并有研究表明SRSF3通过血清反应因子调节结直肠癌的血管生成^[59]。RNA结合蛋白10 (RNA binding motif protein 10, RBM10) 是位于核散斑体中的一种核RNA结合蛋白, 调节初级转录物的选择性剪接^[60]。RBM10突变或RBM10表达降低也已在各种癌症中得到证实, 如肺腺癌和成人膀胱癌、结肠直肠癌、胆管癌和肝细胞癌, 以及脑肿瘤脑膜瘤和成星细胞瘤等。RBM10通常作为肿瘤抑制因子发挥作用; 然而, 它也可能发挥相反的致癌功能^[61]。

存在于核散斑体中的非编码RNA包括剪接体小核RNA、7SK RNA (其下调导致核斑点组分的错误定位) 和长链非编码RNA转移相关肺癌转录物1 (metastasis associated lung adenocarcinoma transcript 1, MALAT1)。MALAT1通过调节剪接因子的磷酸化和由此产生的核分布来影响选择性剪接^[56]。MALAT1被证明与许多癌症相关, 已经在乳腺癌中检测到MALAT1的多种选择性剪接变体, MALAT1在癌细胞中的过表达与肿瘤的增殖、侵袭和转移以及宿主免疫应答的严重损害相关^[62]; 在胃腺癌中发现MALAT1的上调可能与胃癌细胞的肿瘤发生和侵袭性有关^[63]。Hou等^[64]研究表明, MALAT1不仅是癌症治疗的潜在靶点, 也是克服癌症耐药性的潜在靶点。因此, 靶向MALAT1治疗不仅对肿瘤治疗本身有效, 而且使化疗更有效, 这可能有助于癌症的综合治疗并改善癌症的预后。

4 旁斑

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旁斑是一种建立在长链非编码RNA核富集转录体1 (nuclear enriched abundant transcript 1, NEAT1, 也称为MEN-ε/β或VINC-1) 上的核浓缩物。最近, 超分辨率显微镜加上多色标记的旁斑组件(NEAT1 RNA和旁斑蛋白) 揭示旁斑被组织为有序的核-壳结构^[65]。旁斑核心是由果蝇行为人类剪接(Drosophila behavior/human splicing, DBHS) 蛋白、肉瘤融合(fused in sarcoma, FUS) 蛋白和NEAT1 (特别是NEAT1_2 22.3 kb同种型) 之间的相互作用形成的。NEAT1_2是旁斑的主要结构组成部分, 其表达既是旁斑形成的绝对要求, 也是旁斑形成的独有条件^[66]。旁斑包含许多蛋白(> 40种) 并广泛参与RNA代谢, 包括通过蛋白质螯合进行转录调节、A-to-I编辑的RNA转录物的核保留以调节翻译, 以及在细胞应激期间促进存活^[67]。除此之外, 旁斑也参与细胞分化、黄体形成和癌症进展。

旁斑在癌症的发生发展中是双面的。一方面, 旁斑被视为促进癌症的发展。已经证明旁斑参与CML的发展。旁斑的形成本身会改变旁斑内蛋白的分布。富含脯氨酸和谷氨酰胺的剪接因子(splicing factor proline and glutamine rich gene, SPFQ) 作为一种转录因子, 激活几个凋亡基因, 如B淋巴细胞瘤-2基因(B-cell lymphoma-2, BCL2) 结合成分3和BCL2相关X蛋白。当SPFQ保留在旁斑中时, 凋亡蛋白的表达被阻止^[9]。在CML中, BCR-ABL融合基因激活了细胞周期进入和增殖代谢的主要调节因子(c-Myc)。这反过来会抑制NEAT1, 抑制旁斑的形成, 使SPFQ不再被隔离在旁斑中, 促进细胞凋亡。这意味着破坏这一过程有助于CML的发展。因此, CML中异常的旁斑形成导致肿瘤对化疗或放疗诱导的细胞凋亡变得更具抵抗力^[68]。旁斑是一种应激诱导的核体, 其形成会对病毒感染或促炎刺激做出反应。在人肝细胞癌, NEAT1和含非POU域八聚体结合蛋白(non-POU domain-containing octamer-binding protein, NONO) 表达增加。最新研究报道了IL-6信号增加肝癌细胞中旁斑的形成。通过沉默旁斑关键成分NEAT1_2或NONO破坏其形成, 可抑制IL-6诱导的肝癌细胞STAT3磷酸化, 从而抑制IL-6促进的肝癌细胞体外侵袭、细胞周期进程和存活。因此, 旁斑有助于炎症相关的肝癌进展, 并可能成为肝癌的潜在治疗靶点^[69]。Bhatt等^[66]证明与非致瘤细胞系MCF-10A相比, MCF-7乳腺癌细胞中旁斑形成会显著增加, 并与不良预后有关。

另一方面, 旁斑也被证明可以抑制肿瘤形成, 这依赖于与p53蛋白的相互作用^[68]。p53基因在大约一半的人类癌症中发生突变, 这一事实表明p53是许多肿瘤抑制基因中最重要的基因。p53蛋白被各种细胞应激如DNA损伤激活, 导致与DNA修复、细胞周期停滞和凋亡相关的许多靶基因的反式激活^[70]。最近, NEAT1已被证明是这种p53肿瘤抑制途径的非常重要的下游调节剂, 其导致肿瘤抑制和化学抗性降低^{[68, 71]}。事实上, 在NEAT1的启动子中发现了p53结合基序, 并且p53的激活导致NEAT1的表达, 这项研究还表明, NEAT1的衰减导致p53抑制肿瘤的能力降低, 证明NEAT1部分负责p53的肿瘤抑制作用^{[68, 71]}。

Pisani和Baron^[68]指出NEAT1通过成为旁斑的关键结构成分和其他方式, 与基因调控途径相互作用, 引起基因表达的变化, 从而影响肿瘤耐受化疗和形成癌症干细胞的能力。因此, NEAT1的转录水平可能是诊断和预后价值的潜在生物标志物。虽然NEAT1在肿瘤中的许多功能尚不清楚, 但当前的研究指出通过改变NEAT1_1和NEAT1_2这两种3′加工变体比例, 可以有效地降低肿瘤的化疗耐药性^[68]。因此, 加深NEAT1在化疗耐药性中的各种作用研究, NEAT1可能成为潜在的肿瘤治疗靶点。

5 其他核体

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卡哈尔体是在哺乳动物神经元中发现的核结构, 作为小核RNA和小核仁的修饰以及核糖核蛋白复合体的组装和运输的位点。除卷曲蛋白外, 卡哈尔体还富含小核糖核蛋白复合物、小核仁核糖核蛋白、端粒酶核糖体核蛋白复合物以及组装和成熟核糖体核蛋白复合物的因子^[72]。目前, 尽管卡哈尔体功能障碍尚未明确, 但几种卡哈尔体成分的突变已被证实与人类疾病有关。编码端粒酶复合体成员的基因突变导致过早衰老病症、先天性角化不良^[5]。端粒酶核糖体核蛋白复合物具有维持端粒长度的功能, 成熟的端粒酶核糖体核蛋白复合物包括端粒酶RNA、端粒酶反转录酶和其他相关蛋白质。在肿瘤细胞中端粒调节被破坏, 端粒酶活性增强, 致使端粒不发生生理性缩短, 导致肿瘤细胞永生化^[73]。

核应激小体是一种特殊的亚核细胞器, 在响应各种应激条件, 如热休克、紫外线辐射和化学毒性下形成。核应激小体的主要组分可分为蛋白质和非蛋白质对应物, 其中热休克因子1和2 (heat shock factor 1/2, HSF1/HSF2)、支架附着因子B、有丝分裂中Src相关68 kDa蛋白及SRSF1、SRSF7和SRSF9是蛋白组分。核应激小体的唯一非蛋白质组分是人类卫星Ⅲ长链非编码(RNA satellite Ⅲ lncRNA, SatIII lncRNA), 其作为热休克反应的关键调节剂发挥作用。核应激小体与肿瘤或者其他疾病的关系还并不明确^{[5, 74]}。最近有研究发现, p53与SatIII和HSF1存在相互作用。SatIII lncRNA是细胞应激反应的关键调节因子, 但其在癌症中的功能还有待探索。肿瘤蛋白p53是肿瘤网络的主要调节因子, 如果发生改变, 可能导致化疗耐药性, HSF1是致癌控制和整体细胞应激之间的共同分子, 在热休克时作为癌基因并转录SatIII。这项研究首次推断p53可能是核应激小体的组成部分, 在HSF1和SatIII存在的情况下, 核应激小体可能调节癌症进展期间的细胞应激反应。这提示研究者深入研究SatIII和p53的调控可能为肿瘤细胞凋亡和早期分子靶向治疗开辟新的途径^[75]。

多梳小体是多梳组(polycomb group, PcG) 蛋白的聚集体, 其中DNA的PcG结合区域被定位并彼此接触。多梳小体被认为是PcG介导的转录阻抑的位点, 因为已知的PcG靶基因在它们被阻抑的组织或细胞中特异性地定位于多梳小体。这是否仅仅反映了染色质结合的PcG蛋白的聚集, 或者在基因沉默中具有重要的功能, 甚至可能将基因招募到多梳小体中进行沉默, 还存在争议。但越来越多的证据将多梳小体形成与基因组组织和转录调控联系起来, 但具体的调控机制以及多梳小体与疾病的关系还不明确^[76]。PcG蛋白是一类染色质调节蛋白, 对维持细胞特性至关重要。PcG蛋白可被分为至少3种多蛋白复合物, 即多梳抑制性复合物1和2以及多梳抑制性去泛素酶。肿瘤发生和进展中的表观遗传学畸变已被证明可引起所有典型的癌症标志^[77]。迄今为止, PcG蛋白在实体瘤和血液恶性肿瘤中的作用已被广泛研究。PcG功能的失调可以通过逃避生长抑制、持续增殖信号、细胞死亡抗性、细胞能量和代谢重编程失调、诱导血管生成、激活侵袭和转移、肿瘤促进炎症和避免免疫破坏, 而有助于获得癌症的发生。但与基因突变不同, 表观遗传学改变是可逆的, 对于一部分癌症, PcG蛋白已被证明是最佳的治疗靶点。目前, 已经有数十种药物正在一系列临床试验中^[78]。

由于卡哈尔体、卡哈尔双体、转录工厂(transcription factory)、组蛋白基因座体(histone locus body) 等其他核体与肿瘤之间的关系文献报道还少, 因此本文仅对上述部分核体在肿瘤中的作用进行介绍。

6 结语

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核体种类众多, 形成复杂, 功能多样, 参与各种细胞活动, 如转录、RNA剪接、衰老、凋亡信号和DNA损伤的反应、表观遗传调控、肿瘤发生和抗病毒防御。最新研究表明, 核体在组成、形状和功能方面的显著动态极大地影响染色质状态和组织, 导致响应细胞状态和应激的基因表达改变, 并且与疾病相关, 包括肿瘤。

核体参与肿瘤的发生发展, 并影响肿瘤药物耐药。如作为PML核体的骨架蛋白, PML蛋白参与肿瘤药物耐药。PML已被证明通过维持“静止”肿瘤细胞群来介导白血病对化疗的耐药性。有研究表明, 耐药白血病细胞持续存在是导致白血病治疗后复发的关键因素。在急性和慢性髓细胞白血病中, PML能够调节微环境中间充质干细胞的促炎性细胞因子, 通过非细胞自主性的机制导致耐药^{[79, 80]}。研究人员通过整合临床前研究和Ⅰ期临床试验中患者肿瘤组织的分析, 证明了PML在介导胶质母细胞瘤mTOR和EGFR抑制剂耐药中的重要作用, 提供了mTOR抑制促进患者PML上调以及PML的这种上调介导耐药性的证据^[81]。胰腺导管腺癌的预后不佳主要是由于其对所有常规治疗的快速获得性耐药。Wang等^[50]证明了PML蛋白SUMO化修饰的改变是耐药性机制的一部分, 确定了PML表达和SUMO化水平与肿瘤对抗癌治疗的敏感性之间的相关性; 化疗耐药被认为是急性淋巴细胞白血病(ALL) 治疗无效的主要原因。核仁素(NCL) 作为核仁中高表达的蛋白, 在大多数癌症中发挥致癌作用。有研究提出NCL的表达与ALL的化疗耐药和预后不良呈正相关, NCL可能是改善ALL预后的潜在目标。NCL还会部分通过DNA修复调节提高神经胶质瘤干细胞对替莫唑胺的敏感性^[82]。

同样, 核体相关蛋白也参与肿瘤免疫调节。有研究确定WDR4为一种癌蛋白, 通过泛素化负向调节PML, 从而通过促进免疫抑制和转移的肿瘤微环境促进肺癌进展, 这提示研究者针对具有异常PML降解的肺癌进行免疫调节治疗的潜在可能性^[50]。损伤相关分子模式(damage associated molecular patterns, DAMPs) 有助于癌症化疗期间的抗肿瘤免疫。研究人员鉴定核糖体蛋白RPL15作为与DAMP分泌和抗肿瘤免疫激活相关的新型拓扑替康靶蛋白, 表明核糖体应激是DAMP分泌的触发因素, 有助于抗肿瘤免疫治疗^[83]。

目前, 靶向核体治疗肿瘤的方法可总结为以下3种。一是靶向核体形态结构, 如通过破坏核仁完整性来治疗肿瘤的药物(rDNA嵌入剂、烷基化交联剂等); ATO和ATRA联合治疗逆转癌细胞PML核体的变化, 诱导PML核体重组, 达到治疗APL的目的, 研发专门促进或阻碍PML核体生物合成的药物具有一定的研究价值。二是靶向核体内蛋白或者RNA。核体是富含蛋白和RNA的生物分子凝聚物, 核体的结构以及功能多样性依赖于核体内的众多蛋白和RNA, 如氟喹诺酮衍生物CX-3543通过直接抑制核仁驻留RNA Pol Ⅰ来治疗肿瘤; 肿瘤抑制因子PML蛋白是PML核体的主要组织者, 有研究表明PML通过控制干性和代谢重组而促进肿瘤, 靶向PML蛋白可能是治疗某些肿瘤的有效手段; MALAT1和NEAT1作为核散斑体和旁斑内的重要长链非编码RNA, 被证明是降低肿瘤化疗耐药性的潜在靶点。第三类是靶向核体参与调控的信号通路, 如Myc、Ras/ERK、mTOR和Akt/PKB致癌信号通路汇聚到核仁, 其抑制剂可以用于肿瘤的治疗(表 1)。

值得注意的是, 核体在肿瘤中的作用还没有完全研究清楚, 可能具有一定的肿瘤特异性, 但目前收集到的数据还比较有限, 靶向核体治疗肿瘤还需要更多的实验支撑。但随着技术的进步, 空间多组学方法已经揭示了核仁在调节rDNA和邻近的非rDNA染色质活性中的新作用, 核斑点在支架活性基因组结构中的作用, 以及PML核体在维持应激条件下基因组稳定性中的作用, 这提示在细胞核内核体与染色质之间的复杂关系。深入研究核体在基因组中的作用, 也有助于研究者更好地理解核体与疾病的关系, 为开发靶向核体的肿瘤治疗药物提供一定的理论依据。相信随着具有更高分辨率和体内适用性的空间分辨组学技术的持续开发和整合, 以及对核体更加深入的探索与研究, 研究者可以更好地了解细胞核的时空动态以及核体在病理生理条件下的影响, 为疾病的预防与治疗提供一定的理论依据。

作者贡献: 刘蕴瑶负责确定选题、拟定论文框架和对稿件进行初步校验、论文修改; 刘清远、许义婷、许宇饺负责文献调研及论文撰写; 强磊负责论文整个选题和写作过程的指导、把关, 以及论文的修改和定稿。

利益冲突: 所有作者声明不存在利益冲突。

基金

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国家自然科学基金资助项目(81974425)
江苏省自然科学基金(BK20210419)
江苏省自然科学基金资助项目(BK20211578)

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2024年第59卷第12期

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doi: 10.16438/j.0513-4870.2024-0597

接收时间：2024-06-25
首发时间：2025-11-24
出版时间：2024-12-12

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收稿日期：2024-06-25
修回日期：2024-09-23

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国家自然科学基金资助项目(81974425)

江苏省自然科学基金(BK20210419)

江苏省自然科学基金资助项目(BK20211578)

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中国药科大学基础医学与临床药学学院, 江苏南京 210000

通讯作者:

^*刘蕴瑶, Tel: 15150686765, E-mail: 15150686765@163.com;

强磊, Tel: 86-25-86185641, E-mail: lqiang@cpu.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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Mechanism of action	Drugs that targets the nuclear bodies	Class of compounds	Cancer type
Topoisomerase Ⅰ inhibition	Topotecan	Camptothecins	Ovarian cancer, small cell lung cancer, or cervical cancer
Irinotecan	Camptothecins	Metastatic carcinoma of the colon or rectum and pancreatic adenocarcinoma
Topoisomerase Ⅱ inhibition	Etoposide	Epipodophyllotoxins	Sarcoma, glioblastoma, lung, testicular, haematological cancers
Teniposide	Epipodophyllotoxins	Refractory childhood acute lymphoblastic leukemia
Mitoxantrone	Anthraquinone	Acute myeloid leukemia, hepatocellular carcinoma, breast cancer
Amsacrine	Acridine	Tumor
Doxorubicin	Anthracycline	Haematological cancers, bladder, breast, stomach, lung, ovarian and thyroid cancer, sarcoma
Idarubicin	Anthracycline	Acute myeloid leukemia
DNA intercalating agent	Daunorubicin	Anthracycline	Nonlymphocytic leukemia and acute lymphocytic leukemia
Actinomycin D	Antibiotic	Wilms' tumour, sarcoma
rDNA crosslinking agent	Cisplatin/oxaliplatin	Platinum compound	Sarcoma, lymphoma, carcinoma
Mitomycin C	Antibiotic	Stomach or pancreatic adenocarcinoma; anal, bladder, breast, cervical, colorectal, head, non-small-cell lung cancer
Disrupting nucleolar integrity	Roscovitine/olomoucine DRB	CDK inhibitors	Adenocarcinoma, B-cell malignancies, breast cancer
Inhibiting RNA Pol I activity	Quinacrine	Selective inhibitor of RNA Pol I	Acute myeloid leukemia
CX-5461	Selective inhibitor of RNA Pol I	Haematological cancers
9-Hydroxyellipticine (9HE)	Selective inhibitor of RNA Pol I	Breast cancer
Thymidylate synthase/rRNA/rDNA synthesis inhibitor	5-Fluorouracil	Pyrimidine nucleotide analogue	Colon, rectum, head, neck cancers
Inhibiting mTOR signalling resulting in inhibition of ribosome biogenesis	Everolimus	mTOR signalling inhibitor	Renal cell carcinoma, breast cancer and lymphoma
Inhibiting AKT signalling resulting in suppression of rDNA gene transcription	AKTi-1/2/MK-2206	AKT signalling inhibitor	Non-small-cell lung cancer
Inhibiting the MDM2-P53 interaction	JNJ-26854165	Tryptamine derivative	Solid tumours
AMG 232	Piperidinone derivative	Breast cance
Forced degradation of PML/RARα and induction of PML nucleosome assembly	ATO and ATRA	Arsenic compound and vitamin A acid	Acute promyelocytic leukemia
Double targeting mitochondria cooperatively clears acute myeloid leukemia and prolongs survival by targeting PML	Venetoclax and actinomycin D	Selective inhibitor of BCL2 and antibiotic	Acute myeloid leukemia
Target mitochondria, release mtDNA, activate cGAS signal pathway and promote ROS production, restore PML nucleosome formation	Actinomycin D	Antibiotic	Acute myeloid leukemia with recurrent/refractory NPM1 mutation

Mechanism of action

Drugs that targets the nuclear bodies

Class of compounds

Cancer type

Topoisomerase Ⅰ inhibition

Topotecan

Camptothecins

Ovarian cancer, small cell lung cancer, or cervical cancer

Irinotecan

Camptothecins

Metastatic carcinoma of the colon or rectum and pancreatic adenocarcinoma

Topoisomerase Ⅱ inhibition

Etoposide

Epipodophyllotoxins

Sarcoma, glioblastoma, lung, testicular, haematological cancers

Teniposide

Epipodophyllotoxins

Refractory childhood acute lymphoblastic leukemia

Mitoxantrone

Anthraquinone

Acute myeloid leukemia, hepatocellular carcinoma, breast cancer

Amsacrine

Acridine

Tumor

Doxorubicin

Anthracycline

Haematological cancers, bladder, breast, stomach, lung, ovarian and thyroid cancer, sarcoma

Idarubicin

Anthracycline

Acute myeloid leukemia

DNA intercalating agent

Daunorubicin

Anthracycline

Nonlymphocytic leukemia and acute lymphocytic leukemia

Actinomycin D

Antibiotic

Wilms' tumour, sarcoma

rDNA crosslinking agent

Cisplatin/oxaliplatin

Platinum compound

Sarcoma, lymphoma, carcinoma

Mitomycin C

Antibiotic

Stomach or pancreatic adenocarcinoma; anal, bladder, breast, cervical, colorectal, head, non-small-cell lung cancer

Disrupting nucleolar integrity

Roscovitine/olomoucine DRB

CDK inhibitors

Adenocarcinoma, B-cell malignancies, breast cancer

Inhibiting RNA Pol I activity

Quinacrine

Selective inhibitor of RNA Pol I

Acute myeloid leukemia

CX-5461

Selective inhibitor of RNA Pol I

Haematological cancers

9-Hydroxyellipticine (9HE)

Selective inhibitor of RNA Pol I

Breast cancer

Thymidylate synthase/rRNA/rDNA synthesis inhibitor

5-Fluorouracil

Pyrimidine nucleotide analogue

Colon, rectum, head, neck cancers

Inhibiting mTOR signalling resulting in inhibition of ribosome biogenesis

Everolimus

mTOR signalling inhibitor

Renal cell carcinoma, breast cancer and lymphoma

Inhibiting AKT signalling resulting in suppression of rDNA gene transcription

AKTi-1/2/MK-2206

AKT signalling inhibitor

Non-small-cell lung cancer

Inhibiting the MDM2-P53 interaction

JNJ-26854165

Tryptamine derivative

Solid tumours

AMG 232

Piperidinone derivative

Breast cance

Forced degradation of PML/RARα and induction of PML nucleosome assembly

ATO and ATRA

Arsenic compound and vitamin A acid

Acute promyelocytic leukemia

Double targeting mitochondria cooperatively clears acute myeloid leukemia and prolongs survival by targeting PML

Venetoclax and actinomycin D

Selective inhibitor of BCL2 and antibiotic

Acute myeloid leukemia

Target mitochondria, release mtDNA, activate cGAS signal pathway and promote ROS production, restore PML nucleosome formation

Actinomycin D

Antibiotic

Acute myeloid leukemia with recurrent/refractory NPM1 mutation