Hypoxia tolerance of cancer cells through suppression of mTOR signaling

通过抑制 mTOR 信号传导提高癌细胞的缺氧耐受性

• 批准号: 17590284
• 负责人: INOUE Masahiro
• 金额: $ 2.3万
• 依托单位: Osaka Medical Center for Cancer and Cardiovascular Diseases Osaka Prefectural Hospital Organization
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590284/
• 关键词: hypoxia; mTOR; PI3K; apoptosis; P13K

mTOR (mammalian target of rapamycin) is activated and contributes to proliferation and survival of cancer cells under oxygenated and nutritionally rich conditions. On the other hand, under hypoxic and nutritionally poor conditions, mTOR signal is suppressed, although the physiological role of the suppression had not been clarified. This study aimed at elucidating the correlation between the suppression of mTOR signaling and cancer cell survival under hypoxic conditions.First, we examined the molecular mechanism in vitro. In a colon cancer cell line, COLO 320, which is hypoxia sensitive, over-expression of Rheb as well as eIF4E activated mTOR signaling even under hypoxic conditions. Rheb and eIF4E introduced cells were more sensitive to hypoxia. The death was circumvented by inhibition of PI3K or mTOR. On the other hand, in a pancreas cancer cell line, AsPC-1, which is hypoxia tolerant, neither rheb nor eIF4E could activate mTOR signaling under hypoxic conditions. We also tried TAT-ODD system equipped with active form of Rheb. AsPC-1 cells treated with TAT-ODD-rheb could not stimulate mTOR signaling under hypoxic conditions. Together, in AsPC-1 cells, other factors in addition to rheb are necessary to activate mTOR signaling under hypoxic conditions.We found that IGF stimulation generated massive apoptosis in COLO 320 cells in hypoxia as well as AsPC-1 cells in anoxia. IGF induced robust endoplasmic reticulum stress, ER stress, under hypoxic conditions, and the ER stress was necessary for apoptosis. Especially, we revealed that CHOP induction was critical for the cell death (Cancer Research, in revision). We also found that phosphorylation of S6, a downstream event of mTOR activation, was suppressed under hypoxic area compared with well oxygenized area. Since, we could not activate mTOR signaling under hypoxic area in vivo, the role of mTOR suppression in vivo remains to be elucidated.

mTOR（雷帕霉素的哺乳动物靶标）被激活，并有助于癌细胞在含氧和营养丰富的条件下的增殖和存活。另一方面，在缺氧和营养不良的条件下，mTOR信号被抑制，尽管这种抑制的生理作用尚未阐明。本研究旨在阐明缺氧条件下mTOR信号抑制与癌细胞存活之间的相关性。在结肠癌细胞系科洛320中，其是缺氧敏感的，Rheb以及eIF 4 E的过表达甚至在缺氧条件下激活mTOR信号传导。Rheb和eIF 4 E导入的细胞对缺氧更敏感。通过抑制PI 3 K或mTOR避免了死亡。另一方面，在耐缺氧的胰腺癌细胞系AsPC-1中，rheb和eIF 4 E都不能在缺氧条件下激活mTOR信号传导。我们还尝试了配备活性形式Rheb的TAT-ODD系统。TAT-ODD-rheb处理的AsPC-1细胞在缺氧条件下不能刺激mTOR信号。总之，在AsPC-1细胞中，除了rheb之外，其他因子也是在缺氧条件下激活mTOR信号传导所必需的。我们发现，IGF刺激在缺氧条件下的科洛320细胞和缺氧条件下的AsPC-1细胞中产生了大量细胞凋亡。IGF在缺氧条件下诱导了强烈的内质网应激，ER应激是细胞凋亡所必需的。特别地，我们揭示了CHOP诱导对于细胞死亡是至关重要的（Cancer Research，修订版）。我们还发现，S6的磷酸化，mTOR激活的下游事件，被抑制缺氧区相比，充分氧合区。由于我们不能在体内缺氧区域激活mTOR信号，因此mTOR抑制在体内的作用仍有待阐明。

项目成果

Cross talk between apoptosis and invasion signaling in cancer cells through casupase-3 activation.

通过 casupase-3 激活癌细胞中细胞凋亡和侵袭信号之间的交互作用。

• 发表时间: 2005
• 期刊: Cancer Res 65
• 作者: Mukai M;Kusama T;Hamanaka Y;et al.
• 通讯作者: et al.

Suppression of PI3K/mTOR pathway rescues LLC cells from cell death induced by hypoxia.

• DOI: 10.1016/j.bbrc.2005.02.163
• 发表时间: 2005-04
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Y. Hamanaka;M. Mukai;M. Shimamura;T. Kitagawa;T. Nishida;F. Isohashi;T. Ito;Y. Nishizawa;M. Tatsuta;H. Matsuda;M. Inoue

Inhibition of transendothelial migration and invasion of human breast cancer cells by preventing geranylgeranylation of Rho

通过阻止Rho香叶基香叶基化抑制人乳腺癌细胞的跨内皮迁移和侵袭

• 发表时间: 2006
• 期刊: International Journal of Oncology 29.1
• 作者: Kusama T;Mukai M;Tatsuta M.;et al.
• 通讯作者: et al.

Inactivation of Rho GTPases by p190 RhoGAP reduces human pancreatic cancer cell invasion and metastasis

• DOI: 10.1111/j.1349-7006.2006.00242.x
• 发表时间: 2006-09-01
• 期刊: CANCER SCIENCE
• 影响因子: 5.7
• 作者: Kusama, Toshiyuki;Mukai, Mutsuko;Inoue, Masahiro
• 通讯作者: Inoue, Masahiro

CD4+ T cell-mediated antigen-specific immunotherapy in a mouse model of cervical cancer

• DOI: 10.1158/0008-5472.can-04-3444
• 发表时间: 2005-03-01
• 期刊: CANCER RESEARCH
• 影响因子: 11.2
• 作者: Daniel, D;Chiu, C;Hanahan, D
• 通讯作者: Hanahan, D