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

Abstract

IntroductionmTOR 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 methodsA498 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 conclusionWe 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 HIF1α 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 HIF1α impaired both antagonist-elicited apoptoses to differential extents, corresponding to their expression changes responding to chemical treatments, and double knockdown of p53 and HIF1α remarkably hindered MI-319- or rapamycin-induced apoptosis, suggesting that both p53 and HIF1α are involved in MDM2 or mTOR antagonist-induced apoptosis. Collectively, we propose that concurrent activation of p53 and HIF1α may effectively result in cancer-cell apoptosis, and that combined MDM2 antagonists and mTOR inhibitors may be useful in RCC therapy.

Prognostic value of CDCA3 in kidney renal papillary cell carcinoma

“…Galectin-3 is widely expressed in RCC, and promotes the invasiveness, and suggestiveness via CXCR2, thereby affecting the occurrence and development of RCC [ 28 ]. Activation of p53 and HIF-1α promoted the transformation of RCC cells [ 29 ]. Peckova et al found that most KIRP cells exhibit polysomy of chromosome 17 and chromosome 7 and expressed AMACR, OSCAR, CAM 5.2, HIF-2, and vimentin [ 30 ].…”

Targeting Strategies for Renal Cell Carcinoma: From Renal Cancer Cells to Renal Cancer Stem Cells

“…Activation of the mTOR pathway leads to translation of proteins involved in cell cycle progression and HIF-1α expression, which is associated with RCC pathogenesis. On the other hand, mTOR inhibitors whose mechanism of action is distinct from that of the TKIs mentioned above, halt tumor cell growth and angiogenesis by down-regulating HIF expression and blocking proliferation and survival signals downstream of the VEGF receptor (Kornakiewicz et al, 2014; Liu et al, 2016). Temsirolimus and everolimus are orally administered mTOR inhibitors used for targeted therapy in metastatic renal cell carcinoma (mRCC).…”