肿瘤细胞抗脱落凋亡分子机理及其人工干预的初步研究
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摘要
脱落凋亡(anoikis)是凋亡的一种形式，它是由于正常的上皮细胞或内皮细胞脱离与ECM的联系而引起的。其生物学意义在于防止这些脱落的细胞种植于其他不适当的地方继续生长。大多数来源于上皮或内皮组织的肿瘤细胞，尤其是容易发生转移的恶性肿瘤细胞，则失去了这种特性，由于瘤细胞从瘤体上脱落后并不发生凋亡，因而可以种植到其他部位继续生长。这种存在于某些肿瘤细胞中的对脱落凋亡的敏感性降低被认为是肿瘤发生转移的一个重要机制。转移瘤的发生是临床上肿瘤病人死亡的一个重要原因，而且这种现象极其多见，例如乳腺癌、肺癌、肝癌、胃癌、前列腺癌等恶性肿瘤都很容易发生转移。因此，阐明肿瘤细胞抗脱落凋亡现象的信号转导过程将会是一项非常有前景的研究课题。一方面对于理解参与脱落凋亡和抗脱落凋亡过程的信号分子和信号转导途径具有重要的理论意义，另一方面对于发展抑制肿瘤转移新策略同样具有重要的应用价值。
为深入理解肿瘤细胞抗脱落凋亡的分子机制，我们首先通过DNA ladderring检测、FCM检测以及软琼脂集落形成实验筛选了一些乳腺癌细胞系，包括Bcap-37、MCF-7、MDA-NB-231以及SK-BR-3，观察它们对脱落凋亡的敏感性。结果显示，来源于狗正常肾脏上皮的阳性对照MDCK细胞对脱落凋亡是敏感的，表现为琼脂糖凝胶电泳检测到凋
第四军医大学博士学位论文 第6页
亡特征性的片段化DNA，细胞周期中高比例的亚二倍体峰的出现，以及在软琼脂中不
能形成集落。而Bcap－37、MCF－7、MDA－n－231三种乳腺癌细胞则具有抗脱落凋亡的特
性，分别与它们各自贴壁培养的细胞比较，胞浆DNA琼脂糖凝胶电泳表现无明显差异，
FCM所检测到的凋亡峰也无明显区别。而且，这三种乳腺癌细胞在软琼脂中都具有形
成集落的能力。SK．BR－3细胞同样是抗脱落凋亡的；但它却不能在软琼脂中形成集落，
也许与ECM联系的失去对SK－BR－3细胞的悬浮生长有一定的影响。
对于筛选出的三种抗脱落凋亡的肿瘤细胞系，它们的抗脱落凋亡特性究竟与哪个
或哪些信号分子有关呢？首先，我们观察了一些信号分子的特异抑制剂对肿瘤细胞抗
脱落凋亡特性的影响，期望通过对脱落凋亡的抑制来提示我们与脱落凋亡相关的信号
分子。其中包括：HERZ的特异抑制剂AG825；，PDGFR的特异抑制剂AG17；p38MAPK
的特异抑制剂sB203580：＊D－K的特异抑制剂LY 29以m2；MAP KK（K）的特异抑
制剂PD98059。胞浆DNA电泳显示在短时间内（15h），这些抑制剂未能诱导悬浮培养
的肿瘤细胞出现凋亡现象，但在软琼脂集落形成实验中，每种抑制剂对肿瘤细胞在软
琼脂中的生长则具有不同的影响。AG17对三种乳腺癌细胞均有明显的抑制作用，
PD98059可以部分抑制MDA－MB－231的集落形成。其余的抑制剂则没有明确的生长
抑制现象。这些结果提示我们，PDGFR信号通路可能与三种乳腺癌细胞的抗脱落凋亡
特性相关。另外对于 MDA．MB．231细胞来说，MAPK信号转导通路在其抗脱落凋亡
过程中也许起着一定的作用。由于信号转导网络系统的复杂性，这两种信号转导通路
究竟扮演着什么样的角色尚待进一步的研究。
在抑制剂分析实验中，作用比较明确的是广谱蛋白酪氨酸激酶抑制剂genistein，
尽管短期（24小时内）作用不是很明显，胞浆DNA琼脂糖凝胶电泳以及FCM均未
能检测到它对悬浮培养的三种乳腺癌细胞的诱导凋亡作用。但它可以完全抑制它们在
软琼脂中的生长，经 western blotting检测，在 genistein的作用下细胞中总体蛋白酪氨
酸的磷酸化水平也有不同程度的下降。这提示我们肿瘤细胞的抗脱落凋亡特性很可能
仍然是由蛋白酪氨酸激酶来介导的。
我们进一步检测了几种相关信号通路中的关键信号分子在贴壁培养与悬浮培养
时的表达水平及磷酸化状态的改变。发现两种重要的参与细胞存活信号通路的信号分
子ERKI／2以及AKT（分别参与MAPK信号通路以及PD－K信号通路）的表达水平在
Doann’Uat ofBtochemtw and ilecUler Btotort FMMU
第四军医大学博士学位论文 第7页
贴壁细胞与悬浮细胞中没有明显的差异。但是未能检测到它们磷酸化水平的差异，因
而它们是否参与所检测的三种乳腺癌细胞抗脱落凋亡的过程尚不能明确。FAK的磷酸
化水平在悬浮培养的细胞中是下降的，这与文献报导一致。衔接分子 PI 30CAS在悬浮
培养的乳腺癌细胞中的表达水平与贴壁培养的细胞比较有不同程度的增加，尤其是在
MDA－MB－23细胞中，随着悬浮培养的时间延长，这种趋势更为明显。
我们同时检测了三种乳腺癌细胞在悬浮培养时总体蛋白酪氨酸磷酸化水平的改
变。大多数蛋白酪氨酸磷酸化的水平在悬浮培养的乳腺癌细胞中是下降的。例外的是
在悬浮培养的BCap－37细胞以及MDA－MB－231细胞中，在66二kD与97．4kD之间有一
条带，其磷酸化水平与贴壁培养的细胞相比明显增高。此外，在 MDA－MB－23细胞
中，有一大分子量（100kD以上）的分子的酪氨酸磷酸化水平在悬浮培养时明显?
Anoikis is a form of apoptosis triggered by disruption of cell-matrix contacts. It is often seen in normal epithelial and endothelial cells. The significance of anoikis is that it may prevent the accidentally detached cells from reattaching to new matrices and growing dysplastically. On the other hand, most tumor cells derived from epithelial tissues have lost this characteristic, especially those malignant tumors that are easy to metastasize. The cells detached from tumors do not undergo apoptosis and can colonize elsewhere and grow. It is an important mechanism of tumor's metastasis, which attributes to clinical death of most of tumor patients and is often seen in breast, lung, hepatic, gastric and prostate tumors. Therefore, it is important to elucidate the molecular mechanism of tumor cells' anoikis resistance. It will help us to understand the molecules and pathways related to this phenomenon and it has a practical value for developing new strategies to prevent tumor metastasis.
To understand the molecular mechanism of tumor cell resistance of anoikis, we first analyzed several breast cancer cell lines, including Bcap-37, MCF-7, MDA-MB-231 and SK-BR-3, to determine their sensitivity to anoikis through DNA laddering assay, FCM and soft agar assay. The results showed that the MDCK cells, which are derived from normal canine kidney, are sensitive to anoikis. Fragmented DNA could be detected by agarose gel
Department of Biochemistry and Molecular Biology, FMMU
10
electrophoresis. High proportion of cells was in Sub-Gl phase of eel] cycle and the cells could not grow in soft agar to form colonies. On the contrary, the three breast cancer cell lines, Bcap-37, MCF-7 and MDA-MB-231, are anoiMs resistant, as indicated by DNA laddering and FCM assays. Furthermore, they all grow in soft agar and form colonies. SK-BR-3 cells are also anoikis resistant, but it could not form colonies in soft agar. Therefore, detachment may have some effects on the growth of SK-BR-3 cell cultured in suspension.
Next we tried to find out which signaling molecules in the selected three tumor cell lines are related to their resistance to anoikis. We first investigated the effects of specific inhibitors of several signaling molecules on the tumor cell resistance of anoikis. These are KER2 inhibitor AG825; PDGFR inhibitor AG17; P38MAPK inhibitor SB203580; PD-K inhibitor LY294002 and MAPKK (MEK) inhibitor PD98059. Agrose gel electrophoresis showed that these inhibitors failed to induce suspended tumor cells to undergo apoptosis in a short time (15h). But they had different effects on tumor cells grew in soft agar. AG17 could inhibit the growth of three tumor cell Lines apparently and PD98059 could inhibit MDA-MB-231 cell forming colonies partially. The rest had no apparent effect on cell growth. These results imply that PDGFR may be involved in anchorage-independent growth of the tumor cells. MAPK signaling pathway may play a role hi the process of MDA-MB-231 cell's resistance to anoikis. Because of the complexity of signal transduction networks, the importance of these two signaling pathways in tumor cells' resistance to anoikis are need to be further studied.
The effect of the general protein tyrosine kinase inhibitor genistein on tumor cell anoikis resistance was also analyzed. Although the effect of genistein on anoikis was not apparent in a short time (less than 24h), as indicated by both agrose gel electrophoresis assay and FCM assay, genistein could inhibit the growth of the tumor cells in soft agar completely. The total levels of protein tyrosine phosphorylation in the three tumor cells upon genistein treatment were also decreased to some extent. These data imply that the tumor cell resistance to anoikis is mediated by protein tyrosine kinases.
Department of Biochemistry and Molecular Biology, FMMU
Furthermore, we analyzed the changes in expression and phosphorylation of key signaling molecules in several related signal transduction pathways. We found that two important survival signaling molecules, ERK1/2 and AKT, h
为深入理解肿瘤细胞抗脱落凋亡的分子机制，我们首先通过DNA ladderring检测、FCM检测以及软琼脂集落形成实验筛选了一些乳腺癌细胞系，包括Bcap-37、MCF-7、MDA-NB-231以及SK-BR-3，观察它们对脱落凋亡的敏感性。结果显示，来源于狗正常肾脏上皮的阳性对照MDCK细胞对脱落凋亡是敏感的，表现为琼脂糖凝胶电泳检测到凋
第四军医大学博士学位论文 第6页
亡特征性的片段化DNA，细胞周期中高比例的亚二倍体峰的出现，以及在软琼脂中不
能形成集落。而Bcap－37、MCF－7、MDA－n－231三种乳腺癌细胞则具有抗脱落凋亡的特
性，分别与它们各自贴壁培养的细胞比较，胞浆DNA琼脂糖凝胶电泳表现无明显差异，
FCM所检测到的凋亡峰也无明显区别。而且，这三种乳腺癌细胞在软琼脂中都具有形
成集落的能力。SK．BR－3细胞同样是抗脱落凋亡的；但它却不能在软琼脂中形成集落，
也许与ECM联系的失去对SK－BR－3细胞的悬浮生长有一定的影响。
对于筛选出的三种抗脱落凋亡的肿瘤细胞系，它们的抗脱落凋亡特性究竟与哪个
或哪些信号分子有关呢？首先，我们观察了一些信号分子的特异抑制剂对肿瘤细胞抗
脱落凋亡特性的影响，期望通过对脱落凋亡的抑制来提示我们与脱落凋亡相关的信号
分子。其中包括：HERZ的特异抑制剂AG825；，PDGFR的特异抑制剂AG17；p38MAPK
的特异抑制剂sB203580：＊D－K的特异抑制剂LY 29以m2；MAP KK（K）的特异抑
制剂PD98059。胞浆DNA电泳显示在短时间内（15h），这些抑制剂未能诱导悬浮培养
的肿瘤细胞出现凋亡现象，但在软琼脂集落形成实验中，每种抑制剂对肿瘤细胞在软
琼脂中的生长则具有不同的影响。AG17对三种乳腺癌细胞均有明显的抑制作用，
PD98059可以部分抑制MDA－MB－231的集落形成。其余的抑制剂则没有明确的生长
抑制现象。这些结果提示我们，PDGFR信号通路可能与三种乳腺癌细胞的抗脱落凋亡
特性相关。另外对于 MDA．MB．231细胞来说，MAPK信号转导通路在其抗脱落凋亡
过程中也许起着一定的作用。由于信号转导网络系统的复杂性，这两种信号转导通路
究竟扮演着什么样的角色尚待进一步的研究。
在抑制剂分析实验中，作用比较明确的是广谱蛋白酪氨酸激酶抑制剂genistein，
尽管短期（24小时内）作用不是很明显，胞浆DNA琼脂糖凝胶电泳以及FCM均未
能检测到它对悬浮培养的三种乳腺癌细胞的诱导凋亡作用。但它可以完全抑制它们在
软琼脂中的生长，经 western blotting检测，在 genistein的作用下细胞中总体蛋白酪氨
酸的磷酸化水平也有不同程度的下降。这提示我们肿瘤细胞的抗脱落凋亡特性很可能
仍然是由蛋白酪氨酸激酶来介导的。
我们进一步检测了几种相关信号通路中的关键信号分子在贴壁培养与悬浮培养
时的表达水平及磷酸化状态的改变。发现两种重要的参与细胞存活信号通路的信号分
子ERKI／2以及AKT（分别参与MAPK信号通路以及PD－K信号通路）的表达水平在
Doann’Uat ofBtochemtw and ilecUler Btotort FMMU
第四军医大学博士学位论文 第7页
贴壁细胞与悬浮细胞中没有明显的差异。但是未能检测到它们磷酸化水平的差异，因
而它们是否参与所检测的三种乳腺癌细胞抗脱落凋亡的过程尚不能明确。FAK的磷酸
化水平在悬浮培养的细胞中是下降的，这与文献报导一致。衔接分子 PI 30CAS在悬浮
培养的乳腺癌细胞中的表达水平与贴壁培养的细胞比较有不同程度的增加，尤其是在
MDA－MB－23细胞中，随着悬浮培养的时间延长，这种趋势更为明显。
我们同时检测了三种乳腺癌细胞在悬浮培养时总体蛋白酪氨酸磷酸化水平的改
变。大多数蛋白酪氨酸磷酸化的水平在悬浮培养的乳腺癌细胞中是下降的。例外的是
在悬浮培养的BCap－37细胞以及MDA－MB－231细胞中，在66二kD与97．4kD之间有一
条带，其磷酸化水平与贴壁培养的细胞相比明显增高。此外，在 MDA－MB－23细胞
中，有一大分子量（100kD以上）的分子的酪氨酸磷酸化水平在悬浮培养时明显?
Anoikis is a form of apoptosis triggered by disruption of cell-matrix contacts. It is often seen in normal epithelial and endothelial cells. The significance of anoikis is that it may prevent the accidentally detached cells from reattaching to new matrices and growing dysplastically. On the other hand, most tumor cells derived from epithelial tissues have lost this characteristic, especially those malignant tumors that are easy to metastasize. The cells detached from tumors do not undergo apoptosis and can colonize elsewhere and grow. It is an important mechanism of tumor's metastasis, which attributes to clinical death of most of tumor patients and is often seen in breast, lung, hepatic, gastric and prostate tumors. Therefore, it is important to elucidate the molecular mechanism of tumor cells' anoikis resistance. It will help us to understand the molecules and pathways related to this phenomenon and it has a practical value for developing new strategies to prevent tumor metastasis.
To understand the molecular mechanism of tumor cell resistance of anoikis, we first analyzed several breast cancer cell lines, including Bcap-37, MCF-7, MDA-MB-231 and SK-BR-3, to determine their sensitivity to anoikis through DNA laddering assay, FCM and soft agar assay. The results showed that the MDCK cells, which are derived from normal canine kidney, are sensitive to anoikis. Fragmented DNA could be detected by agarose gel
Department of Biochemistry and Molecular Biology, FMMU
10
electrophoresis. High proportion of cells was in Sub-Gl phase of eel] cycle and the cells could not grow in soft agar to form colonies. On the contrary, the three breast cancer cell lines, Bcap-37, MCF-7 and MDA-MB-231, are anoiMs resistant, as indicated by DNA laddering and FCM assays. Furthermore, they all grow in soft agar and form colonies. SK-BR-3 cells are also anoikis resistant, but it could not form colonies in soft agar. Therefore, detachment may have some effects on the growth of SK-BR-3 cell cultured in suspension.
Next we tried to find out which signaling molecules in the selected three tumor cell lines are related to their resistance to anoikis. We first investigated the effects of specific inhibitors of several signaling molecules on the tumor cell resistance of anoikis. These are KER2 inhibitor AG825; PDGFR inhibitor AG17; P38MAPK inhibitor SB203580; PD-K inhibitor LY294002 and MAPKK (MEK) inhibitor PD98059. Agrose gel electrophoresis showed that these inhibitors failed to induce suspended tumor cells to undergo apoptosis in a short time (15h). But they had different effects on tumor cells grew in soft agar. AG17 could inhibit the growth of three tumor cell Lines apparently and PD98059 could inhibit MDA-MB-231 cell forming colonies partially. The rest had no apparent effect on cell growth. These results imply that PDGFR may be involved in anchorage-independent growth of the tumor cells. MAPK signaling pathway may play a role hi the process of MDA-MB-231 cell's resistance to anoikis. Because of the complexity of signal transduction networks, the importance of these two signaling pathways in tumor cells' resistance to anoikis are need to be further studied.
The effect of the general protein tyrosine kinase inhibitor genistein on tumor cell anoikis resistance was also analyzed. Although the effect of genistein on anoikis was not apparent in a short time (less than 24h), as indicated by both agrose gel electrophoresis assay and FCM assay, genistein could inhibit the growth of the tumor cells in soft agar completely. The total levels of protein tyrosine phosphorylation in the three tumor cells upon genistein treatment were also decreased to some extent. These data imply that the tumor cell resistance to anoikis is mediated by protein tyrosine kinases.
Department of Biochemistry and Molecular Biology, FMMU
Furthermore, we analyzed the changes in expression and phosphorylation of key signaling molecules in several related signal transduction pathways. We found that two important survival signaling molecules, ERK1/2 and AKT, h
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32． Morozevich GI, Kozlova NL, Berman AI. Expression of integrins in human intestinal carcinoma cells differing in substrate specificity of apoptosis. Vopr Med Khim. 1998, 44(1) : 77-83
33． Frisch SM, Vuori K, Ruoslahti E, Chan-Hui PY.Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol. 1996, 134(3) :793-9
34． Farrelly N, Lee Y, Oliver J, et al. ECM regulates apoptosis in mammary epithelium through a control on insulin signaling. J Cell Biol. 1999, 144:1337-1348
35． Rak J, Mitsuhashi Y, Sheehan C,et al. Collateral expression of proangiogenic and tumorigenic properties in intestinal epithelial cell variants selected for resistance to anoikis. Neoplasia 1999, 1(1) :23-30
36． Liu W, Ahmad SA, Reinmuth N, et al. Endothelial cell survival and apoptosis in the tumor vasculature. Apoptosis 2000． 5(4) :323-8
37． Jost M, Huggett TM, Kari C, et al. Matrix-independent survival of human keratinocytes through an EGF receptor/MAPK-Kinase-dependent pathway. Mol Biol Cell. 2001, 12(5) :1519-27
38． Jost M, Class R, Kari C, et al. A central role of Bcl-X(L) in the regulation of keratinocyte survival by autocrine EGFR ligands. J Invest Dermatol. 1999, 112(4) :443-9
39． Kottke TJ, Blajeski AL, Martins LM, Comparison of paclitaxel-,
5-fluoro-2'-deoxyuridine-, and epidermal growth factor (EGF)-induced apoptosis. Evidence for EGF-induced anoikis. J Biol Chem 1999, 274(22) : 15927-36
40． Khwaja A, Rodriguez-Viciana P, Wennstrom S, et al. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J 1997, 16(10) :2783-93
41． Fujio Y, Walsh K Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner. J Biol Chem 1999． 4;274(23) : 16349-54．
42． Attwell S, Roskelley C, Dedhar S.The integrin-linked kinase (ILK) suppresses anoikis. Oncogene 2000． 3;19(33) :3811-5
43． Rytomaa M, Lehmann K, Downward J. Matrix detachment induces caspase-dependent cytochrome c release from mitochondria: inhibition by PKB/Akt but not Raf signalling. Oncogene 2000, 19(39) :4461-8
44． Lallemand F, Mazars A, Prunier C, et al. Smad7 inhibits the survival nuclear factor kappaB and potentiates apoptosis in epithelial cells. Oncogene 2001, 20(7) : 879-84
45． Jeong J, Han I, Lim Y, et al.Rat embryo fibroblasts require both the cell-binding and the heparin-binding domains of fibronectin for survival. Biochem J. 2001, 356(Pt 2) :531-7
46． Danilkovitch A, Donley S, Skeel A, Leonard EJ. Two independent signaling pathways mediate the antiapoptotic action of macrophage-stimulating protein on epithelial cells. Mol Cell Biol. 2000, 20(6) :2218-27
47． Wei L, Yang Y, Yu Q.Tyrosine kinase-dependent, phosphatidylinositol 3'-kinase, and mitogeD-activated protein kinase-independent signaling pathways prevent lung adenocarcinoma cells from anoikis. Cancer Res. 2001, 61(6) :2439-44
48． Cardone MH, Salvesen GS, Widmann C,et al.The regulation of anoikis: MEKK-1 activation requires cleavage by caspases. Cell 1997, 90(2) :315-23
49． Frisch SM, Vuori K, Kelaita D, Sicks S.A role for Jun-N-terminal kinase in anoikis; suppression by bcl-2 and crmA. J Cell Biol. 1996, 35(5) : 1377-82
50． Krestow JK, Rak J, Filmus J, Kerbel RS.Functional dissociation of anoikis-like cell death and activity of stress activated protein kinase. Biochem Biophys Res Common. 1999, 260(1) :48-53
51． Davies MA, Lu Y, Sano T, et al Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis. Cancer Res. 1998, 58(23) :5285-90
52． Lu Y, Lin YZ, LaPushin R, et al. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene 1999, 18(50) :7034-45
53． Yawata A, Adachi M, Okuda H, et al. Prolonged cell survival enhances peritoneal dissemination of gastric cancer cells. Oncogene 1998, 16(20) :2681-6
54． Khwaja A, Downward J. Lack of correlation between activation of Jun-NH2-terminal kinase and induction of apoptosis after detachment of epithelial cells. J Cell Biol. 1997, 139(4) :1017-2372．
55． Jost M, Class R, Kari C, et al. A central role of Bcl-X(L) in the regulation of keratinocyte survival by autocrine EGFR ligands. J Invest Dermatol 1999, 112(4) :443-9
56． Frankel A, Rosen K, Filmus J, Kerbel RS.Induction of anoikis and suppression of human ovarian tumor growth in vivo by down-regulation of bcl-x(l).Cancer Res. 2001, 61(12) :4837-41
57． Rosen K, Rak J, Leung T, et al.Activated Ras prevents downregulation of Bcl-X(L) triggered by detachment from the extracellular matrix. A mechanism of Ras-induced resistance to anoikis in intestinal epithelial cells. J Cell Biol. 2000, 149(2) :447-56
58． Rosen K, Rak J, Jin J, et al. Downregulation of the pro-apoptotic protein Bak is required for the ras-induced transformation of intestinal epithelial cells. Curr Biol. 1998, 8(24) :1331-4
59． Aoudjit F, Vuori K.Matrix attachment regulates Fas-induced apoptosis in endothelial cells: a role for c-flip and implications for anoikis.J Cell Biol 2001, 152(3) :633-43
60． Rytomaa M, Martins LM, Downward J.Involvement of FADD and caspase-8 signalling in detachment-induced apoptosis. Curr BioL 1999, 9(18) : 1043-6
61． Frisch SM.Evidence for a function of death receptor-related, death-domain-containing proteins in anoikis. Curr Biol 1999, 9(18) : 1047-9
62． Grossmann J, Walther K, Artinger M, et al. Apoptotic signahng during initiation of detachment-induced apoptosis ("anoikis") of primary human intestinal epithelial cells. Cell Growth Differ. 2001, 12(3) :147-55
63． Steven MF, Robert AS. Anoikis mechanisms. Curr Opin Cell Biol. 2001,13:555-562
64． Browne KA, Johnstone RW, Jans DA, et al. Filamin(280-kDa actin-binding protein) is a caspase substrate and is also cleaved directly by the cytotoxic T lymphocyte protease granzyme B during apotosis. J Biol Chem. 2000, 275:39262-66
65． Strasser A, Puthalakath H, Bouillry P, et al. The Role of bim, a proapoptotic BH3-only member of the Bcl-2 family in cell-death control. Ann New York Acad Sci. 2000, 917:541-548
66． Puthalakath H,Villunger A, O'Reilly L, et al. Bmf: a novel proapototic Bh3-only protein regulated by interaction with the myosinV actin motor complex and activated by anoikis. Science 2001
67． Okuda H, Adachi M, Miyazawa M, et al. Protein kinase Calpha promotes apoptotic cell death in gastric cancer cells depending upon loss of anchorage. Oncogene 1999, 18(40) :5604-9
68． Li G, Fridman R, Kim HR. Tissue inhibitor of metalloproteinase-1 inhibits apoptosis of human breast epithelial cells. Cancer Res 1999 59(24) :6267-75
69． Vitale M, Di Matola T, Bifulco M, et al. Apoptosis induced by denied adhesion to
extracellular matrix (anoikis) in thyroid epithelial cells is p53 dependent but fails to correlate with modulation of p53 expression. FEBS Lett. 1999, 462(1-2):57-60
70. Di Matola T, Mueller F, Fenzi G, et al. Serum withdrawal-induced apoptosis in thyroid cells is caused by loss of fibronectin-integrin interaction. J Clin Endocrinol Metab. 2000,85(3): 1188-93
71. Ordonez C, Screaton RA, Ilantzis C, Stanners CP. Human carcinoembryonic antigen functions as a general inhibitor of anoikis. Cancer Res. 2000, 60(13):3419-24
72. Chen YH, Lu Y, De Plaen IG,Transcription factor NF-kappaB signals antianoikic function of trefoil factor 3 on intestinal epithelial cells. Biochem Biophys Res Commun. 2000, 274(3):576-82
73. Plath T, Detjen K, Welzel M, et al. A novel function for the tumor suppressor p16(INK4a): induetion of anoikis via upregulation of the alpha(5)beta(1) fibronecfin receptor. J Cell Biol. 2000, 150(6): 1467-78
74．王本祥．现代中药药理学．天津科学技术出版社，1997：1437
75．周振华．中药诱导肿瘤细胞凋亡的研究进展．国外医学中医中药分册．1998，20(3)：3-6
76. Matsuzaki Y, et al. Jpn J Cancer Res. 1996,46(6):170-177
77. Inpharma, 1997, (1099): 22
78. Berry DE,et al.J Org Chem,1992,57:420
79．李凤琴等．癌症，1993，12(3)：200
80．罗继红等．国外医学肿瘤学分册，1997，24(4)：223
81．徐学民等．中草药，1998，29(6)：361
82. Akiyama T, et al. J Biol Chem.1987,262:5592-5595
83. Yamashita Y et al. FEBS Lett. 1991, 288:46-50
84. Katdate M, Osborne MP, Telang NT. Oncol Rep, 1998,5(2):311-315
85. Graziani Y. et al. Ear J Biochem. 1983,135:583-589
86. Yu-Quan Wei, et al. Induction of apoptosis by quercelin: involvement of Heat Shock Protein. Cancer Res. 1994, 54:4952
87. Malias AA,et al. Quercelin mediates the down-regulation of mutant P~(53) in human breast cancer cell line MDA-MB468. Cancer Res. 1994,54:2424
88. Jayasuriya H, et al.J Nat Prod. 1992,55(5)696-698
89．邹恒琴等．中草药．1997，28(7)：437
90. Zafra Polo MC, Gonzalez MC, Estornell E, et al. Acetogenins from Annonaceae, inhibitors of mitochondrial complex Ⅰ. Phytochemistry, 1996, 42(2): 253
91．冯孝章．中草药．1996，27(增刊)：5
92. Yu S, et al. Plant Med. 1997,63:258
93. Li-Chevalier T. Anticancer Drugs. 1995,6(suppl 4): 13
94．阎军峰，李金荣．绞股蓝抗肿瘤作用的研究进展．中医药研究，1996：14(3)：60-62
95． Jeandet P, Bessis R,Maume BF,et al. Effect of enological practices on the resveratrol is one content of wine. J Agric Food Chem. 1995,43(2) :316-9
96． Jang M, Cai L, Udeani GO, Slowing KV, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 1997, 275(5297) :218-20
97． Mgbonyebi OP, Russo J, Russo IH-Antiproliferative effect of synthetic resveratrol on human breast epithelial cells. Int J Oncol. 1998, 12(4) :865-9
98． Clement MV, Hirpara JL, Chawdhury SH, et al. Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. Blood 1998, 92(3) :996-1002
99． Atten MJ, Attar BM, Milson T, Holian O. Resveratrol-induced inactivation of human gastric adenocarcinoma cells through a protein kinase C-mediated mechanism, Biochem Pharmacol 2001, 62(10) : 1423-32
100． Liviero L. Fitoterapia,1994,65(3) :203
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30． Gniadecki R, Jemec GB, Thomsen BM, Hansen M. Relationship between keratinocyte adhesion and death: anoikis in acantholytic diseases. Arch Dermatol Res 1998, 290(10) :528-32
31． Zhu Z, Sanchez-Sweatman O, Huang X, et ahAnoikis and metastatic potential of cloudman S91 melanoma cells. Cancer Res 2001,61(4) : 1707-16
32． Morozevich GI, Kozlova NL, Berman AI. Expression of integrins in human intestinal carcinoma cells differing in substrate specificity of apoptosis. Vopr Med Khim. 1998, 44(1) : 77-83
33． Frisch SM, Vuori K, Ruoslahti E, Chan-Hui PY.Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol. 1996, 134(3) :793-9
34． Farrelly N, Lee Y, Oliver J, et al. ECM regulates apoptosis in mammary epithelium through a control on insulin signaling. J Cell Biol. 1999, 144:1337-1348
35． Rak J, Mitsuhashi Y, Sheehan C,et al. Collateral expression of proangiogenic and tumorigenic properties in intestinal epithelial cell variants selected for resistance to anoikis. Neoplasia 1999, 1(1) :23-30
36． Liu W, Ahmad SA, Reinmuth N, et al. Endothelial cell survival and apoptosis in the tumor vasculature. Apoptosis 2000． 5(4) :323-8
37． Jost M, Huggett TM, Kari C, et al. Matrix-independent survival of human keratinocytes through an EGF receptor/MAPK-Kinase-dependent pathway. Mol Biol Cell. 2001, 12(5) :1519-27
38． Jost M, Class R, Kari C, et al. A central role of Bcl-X(L) in the regulation of keratinocyte survival by autocrine EGFR ligands. J Invest Dermatol. 1999, 112(4) :443-9
39． Kottke TJ, Blajeski AL, Martins LM, Comparison of paclitaxel-,
5-fluoro-2'-deoxyuridine-, and epidermal growth factor (EGF)-induced apoptosis. Evidence for EGF-induced anoikis. J Biol Chem 1999, 274(22) : 15927-36
40． Khwaja A, Rodriguez-Viciana P, Wennstrom S, et al. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J 1997, 16(10) :2783-93
41． Fujio Y, Walsh K Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner. J Biol Chem 1999． 4;274(23) : 16349-54．
42． Attwell S, Roskelley C, Dedhar S.The integrin-linked kinase (ILK) suppresses anoikis. Oncogene 2000． 3;19(33) :3811-5
43． Rytomaa M, Lehmann K, Downward J. Matrix detachment induces caspase-dependent cytochrome c release from mitochondria: inhibition by PKB/Akt but not Raf signalling. Oncogene 2000, 19(39) :4461-8
44． Lallemand F, Mazars A, Prunier C, et al. Smad7 inhibits the survival nuclear factor kappaB and potentiates apoptosis in epithelial cells. Oncogene 2001, 20(7) : 879-84
45． Jeong J, Han I, Lim Y, et al.Rat embryo fibroblasts require both the cell-binding and the heparin-binding domains of fibronectin for survival. Biochem J. 2001, 356(Pt 2) :531-7
46． Danilkovitch A, Donley S, Skeel A, Leonard EJ. Two independent signaling pathways mediate the antiapoptotic action of macrophage-stimulating protein on epithelial cells. Mol Cell Biol. 2000, 20(6) :2218-27
47． Wei L, Yang Y, Yu Q.Tyrosine kinase-dependent, phosphatidylinositol 3'-kinase, and mitogeD-activated protein kinase-independent signaling pathways prevent lung adenocarcinoma cells from anoikis. Cancer Res. 2001, 61(6) :2439-44
48． Cardone MH, Salvesen GS, Widmann C,et al.The regulation of anoikis: MEKK-1 activation requires cleavage by caspases. Cell 1997, 90(2) :315-23
49． Frisch SM, Vuori K, Kelaita D, Sicks S.A role for Jun-N-terminal kinase in anoikis; suppression by bcl-2 and crmA. J Cell Biol. 1996, 35(5) : 1377-82
50． Krestow JK, Rak J, Filmus J, Kerbel RS.Functional dissociation of anoikis-like cell death and activity of stress activated protein kinase. Biochem Biophys Res Common. 1999, 260(1) :48-53
51． Davies MA, Lu Y, Sano T, et al Adenoviral transgene expression of MMAC/PTEN in human glioma cells inhibits Akt activation and induces anoikis. Cancer Res. 1998, 58(23) :5285-90
52． Lu Y, Lin YZ, LaPushin R, et al. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene 1999, 18(50) :7034-45
53． Yawata A, Adachi M, Okuda H, et al. Prolonged cell survival enhances peritoneal dissemination of gastric cancer cells. Oncogene 1998, 16(20) :2681-6
54． Khwaja A, Downward J. Lack of correlation between activation of Jun-NH2-terminal kinase and induction of apoptosis after detachment of epithelial cells. J Cell Biol. 1997, 139(4) :1017-2372．
55． Jost M, Class R, Kari C, et al. A central role of Bcl-X(L) in the regulation of keratinocyte survival by autocrine EGFR ligands. J Invest Dermatol 1999, 112(4) :443-9
56． Frankel A, Rosen K, Filmus J, Kerbel RS.Induction of anoikis and suppression of human ovarian tumor growth in vivo by down-regulation of bcl-x(l).Cancer Res. 2001, 61(12) :4837-41
57． Rosen K, Rak J, Leung T, et al.Activated Ras prevents downregulation of Bcl-X(L) triggered by detachment from the extracellular matrix. A mechanism of Ras-induced resistance to anoikis in intestinal epithelial cells. J Cell Biol. 2000, 149(2) :447-56
58． Rosen K, Rak J, Jin J, et al. Downregulation of the pro-apoptotic protein Bak is required for the ras-induced transformation of intestinal epithelial cells. Curr Biol. 1998, 8(24) :1331-4
59． Aoudjit F, Vuori K.Matrix attachment regulates Fas-induced apoptosis in endothelial cells: a role for c-flip and implications for anoikis.J Cell Biol 2001, 152(3) :633-43
60． Rytomaa M, Martins LM, Downward J.Involvement of FADD and caspase-8 signalling in detachment-induced apoptosis. Curr BioL 1999, 9(18) : 1043-6
61． Frisch SM.Evidence for a function of death receptor-related, death-domain-containing proteins in anoikis. Curr Biol 1999, 9(18) : 1047-9
62． Grossmann J, Walther K, Artinger M, et al. Apoptotic signahng during initiation of detachment-induced apoptosis ("anoikis") of primary human intestinal epithelial cells. Cell Growth Differ. 2001, 12(3) :147-55
63． Steven MF, Robert AS. Anoikis mechanisms. Curr Opin Cell Biol. 2001,13:555-562
64． Browne KA, Johnstone RW, Jans DA, et al. Filamin(280-kDa actin-binding protein) is a caspase substrate and is also cleaved directly by the cytotoxic T lymphocyte protease granzyme B during apotosis. J Biol Chem. 2000, 275:39262-66
65． Strasser A, Puthalakath H, Bouillry P, et al. The Role of bim, a proapoptotic BH3-only member of the Bcl-2 family in cell-death control. Ann New York Acad Sci. 2000, 917:541-548
66． Puthalakath H,Villunger A, O'Reilly L, et al. Bmf: a novel proapototic Bh3-only protein regulated by interaction with the myosinV actin motor complex and activated by anoikis. Science 2001
67． Okuda H, Adachi M, Miyazawa M, et al. Protein kinase Calpha promotes apoptotic cell death in gastric cancer cells depending upon loss of anchorage. Oncogene 1999, 18(40) :5604-9
68． Li G, Fridman R, Kim HR. Tissue inhibitor of metalloproteinase-1 inhibits apoptosis of human breast epithelial cells. Cancer Res 1999 59(24) :6267-75
69． Vitale M, Di Matola T, Bifulco M, et al. Apoptosis induced by denied adhesion to
extracellular matrix (anoikis) in thyroid epithelial cells is p53 dependent but fails to correlate with modulation of p53 expression. FEBS Lett. 1999, 462(1-2):57-60
70. Di Matola T, Mueller F, Fenzi G, et al. Serum withdrawal-induced apoptosis in thyroid cells is caused by loss of fibronectin-integrin interaction. J Clin Endocrinol Metab. 2000,85(3): 1188-93
71. Ordonez C, Screaton RA, Ilantzis C, Stanners CP. Human carcinoembryonic antigen functions as a general inhibitor of anoikis. Cancer Res. 2000, 60(13):3419-24
72. Chen YH, Lu Y, De Plaen IG,Transcription factor NF-kappaB signals antianoikic function of trefoil factor 3 on intestinal epithelial cells. Biochem Biophys Res Commun. 2000, 274(3):576-82
73. Plath T, Detjen K, Welzel M, et al. A novel function for the tumor suppressor p16(INK4a): induetion of anoikis via upregulation of the alpha(5)beta(1) fibronecfin receptor. J Cell Biol. 2000, 150(6): 1467-78
74．王本祥．现代中药药理学．天津科学技术出版社，1997：1437
75．周振华．中药诱导肿瘤细胞凋亡的研究进展．国外医学中医中药分册．1998，20(3)：3-6
76. Matsuzaki Y, et al. Jpn J Cancer Res. 1996,46(6):170-177
77. Inpharma, 1997, (1099): 22
78. Berry DE,et al.J Org Chem,1992,57:420
79．李凤琴等．癌症，1993，12(3)：200
80．罗继红等．国外医学肿瘤学分册，1997，24(4)：223
81．徐学民等．中草药，1998，29(6)：361
82. Akiyama T, et al. J Biol Chem.1987,262:5592-5595
83. Yamashita Y et al. FEBS Lett. 1991, 288:46-50
84. Katdate M, Osborne MP, Telang NT. Oncol Rep, 1998,5(2):311-315
85. Graziani Y. et al. Ear J Biochem. 1983,135:583-589
86. Yu-Quan Wei, et al. Induction of apoptosis by quercelin: involvement of Heat Shock Protein. Cancer Res. 1994, 54:4952
87. Malias AA,et al. Quercelin mediates the down-regulation of mutant P~(53) in human breast cancer cell line MDA-MB468. Cancer Res. 1994,54:2424
88. Jayasuriya H, et al.J Nat Prod. 1992,55(5)696-698
89．邹恒琴等．中草药．1997，28(7)：437
90. Zafra Polo MC, Gonzalez MC, Estornell E, et al. Acetogenins from Annonaceae, inhibitors of mitochondrial complex Ⅰ. Phytochemistry, 1996, 42(2): 253
91．冯孝章．中草药．1996，27(增刊)：5
92. Yu S, et al. Plant Med. 1997,63:258
93. Li-Chevalier T. Anticancer Drugs. 1995,6(suppl 4): 13
94．阎军峰，李金荣．绞股蓝抗肿瘤作用的研究进展．中医药研究，1996：14(3)：60-62
95． Jeandet P, Bessis R,Maume BF,et al. Effect of enological practices on the resveratrol is one content of wine. J Agric Food Chem. 1995,43(2) :316-9
96． Jang M, Cai L, Udeani GO, Slowing KV, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 1997, 275(5297) :218-20
97． Mgbonyebi OP, Russo J, Russo IH-Antiproliferative effect of synthetic resveratrol on human breast epithelial cells. Int J Oncol. 1998, 12(4) :865-9
98． Clement MV, Hirpara JL, Chawdhury SH, et al. Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. Blood 1998, 92(3) :996-1002
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