Synergistic roles of p53 and HIF1α in human renal cell carcinoma-cell apoptosis responding to the inhibition of mTOR and MDM2 signaling pathways

被引:11
作者
Liu, Qing-jun [1 ]
Shen, Hong-liang [1 ]
Lin, Jun [1 ]
Xu, Xiu-hong [1 ]
Ji, Zheng-guo [1 ]
Han, Xiao [1 ]
Shang, Dong-hao [1 ]
Yang, Pei-qian [1 ]
机构
[1] Capital Med Univ, Dept Urol Surg, Beijing Friendship Hosp, 95 Yongan Rd, Beijing 100050, Peoples R China
基金
中国国家自然科学基金;
关键词
renal cell carcinoma; mTOR; MDM2; p53; HIF1; alpha; apoptosis; DUAL PI3K/MTOR INHIBITOR; MAMMALIAN TARGET; MITOCHONDRIAL APOPTOSIS; MEDIATED APOPTOSIS; CANCER-CELLS; RAPAMYCIN; PROTEIN; THERAPY; COMBINATION; PROGRESSION;
D O I
10.2147/DDDT.S88779
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Introduction: mTOR and MDM2 signaling pathways are frequently deregulated in cancer development, and inhibition of mTOR or MDM2 independently enhances carcinoma-cell apoptosis. However, responses to mTOR and MDM2 antagonists in renal cell carcinoma (RCC) remain unknown. Materials and methods: A498 cells treated with MDM2 antagonist MI-319 and/or mTOR inhibitor rapamycin were employed in the present study. Cell apoptosis and Western blot analysis were performed. Results and conclusion: We found that the MDM2 inhibitor MI-319 induced RCC cell apoptosis mainly dependent on p53 overexpression, while the mTOR antagonist rapamycin promoted RCC cell apoptosis primarily through upregulation of HIF1 alpha expression. Importantly, strong synergistic effects of MI-319 and rapamycin combinations at relatively low concentrations on RCC cell apoptosis were observed. Depletion of p53 or HIF1 alpha impaired both antagonist-elicited apoptoses to differential extents, corresponding to their expression changes responding to chemical treatments, and double knockdown of p53 and HIF1 alpha remarkably hindered MI-319- or rapamycin-induced apoptosis, suggesting that both p53 and HIF1 alpha are involved in MDM2 or mTOR antagonist-induced apoptosis. Collectively, we propose that concurrent activation of p53 and HIF1a may effectively result in cancer-cell apoptosis, and that combined MDM2 antagonists and mTOR inhibitors may be useful in RCC therapy.
引用
收藏
页码:745 / 755
页数:11
相关论文
共 56 条
[1]   Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma [J].
Atkins, MB ;
Hidalgo, M ;
Stadler, WM ;
Logan, TF ;
Dutcher, JP ;
Hudes, GR ;
Park, Y ;
Lion, SH ;
Marshall, B ;
Boni, JP ;
Dukart, G ;
Sherman, ML .
JOURNAL OF CLINICAL ONCOLOGY, 2004, 22 (05) :909-918
[2]   mTOR Inhibition Induces Compensatory, Therapeutically Targetable MEK Activation in Renal Cell Carcinoma [J].
Bailey, Sean T. ;
Zhou, Bing ;
Damrauer, Jeffrey S. ;
Krishnan, Bhavani ;
Wilson, Harper L. ;
Smith, Aleisha M. ;
Li, Mingqing ;
Yeh, Jen Jen ;
Kim, William Y. .
PLOS ONE, 2014, 9 (09)
[3]   mTOR activates hypoxia-inducible factor-1α and inhibits neuronal apoptosis in the developing rat brain during the early phase after hypoxia-ischemia [J].
Chen, Hongju ;
Xiong, Tao ;
Qu, Yi ;
Zhao, Fengyan ;
Ferriero, Donna ;
Mu, Dezhi .
NEUROSCIENCE LETTERS, 2012, 507 (02) :118-123
[4]   PKB/Akt Activation Inhibits p53-Mediated HIF1A Degradation That Is Independent of MDM2 [J].
Choy, Mun-Kit ;
Movassagh, Mehregan ;
Bennett, Martin R. ;
Foo, Roger S. -Y. .
JOURNAL OF CELLULAR PHYSIOLOGY, 2010, 222 (03) :635-639
[5]   Prolonged efficacy of mTOR inhibitors in papillary renal cell carcinoma: progression-free survival lasting for over 3 years, a case report and review of the literature [J].
Daste, Amaury ;
Gross-Goupil, Marine ;
Roca, Sophie ;
Bernhard, Jean-Christophe ;
Ravaud, Alain .
TARGETED ONCOLOGY, 2014, 9 (01) :81-84
[6]   The loss of mdm2 induces p53 mediated apoptosis [J].
de Rozieres, S ;
Maya, R ;
Oren, M ;
Lozano, G .
ONCOGENE, 2000, 19 (13) :1691-1697
[7]   EGFR protein overexpression correlates with chromosome 7 polysomy and poor prognostic parameters in clear cell renal cell carcinoma [J].
Dordevic, Gordana ;
Ilijas, Koviljka Matusan ;
Hadzisejdic, Ita ;
Maricic, Anton ;
Grahovac, Blazenka ;
Jonjic, Nives .
JOURNAL OF BIOMEDICAL SCIENCE, 2012, 19
[8]   Targeting mTOR to Overcome Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Resistance in Non-Small Cell Lung Cancer Cells [J].
Fei, Shi-Jiang ;
Zhang, Xu-Chao ;
Dong, Song ;
Cheng, Hua ;
Zhang, Yi-Fang ;
Huang, Ling ;
Zhou, Hai-Yu ;
Xie, Zhi ;
Chen, Zhi-Hong ;
Wu, Yi-Long .
PLOS ONE, 2013, 8 (07)
[9]   The coordinate regulation of the p53 and rnTOR pathways in cells [J].
Feng, ZH ;
Zhang, H ;
Levine, AJ ;
Jin, S .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (23) :8204-8209
[10]   The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein [J].
Feng, Zhaohui ;
Levine, Arnold J. .
TRENDS IN CELL BIOLOGY, 2010, 20 (07) :427-434