Journal
JOURNAL OF TRANSLATIONAL MEDICINE
Volume 16, Issue -, Pages -Publisher
BMC
DOI: 10.1186/s12967-018-1543-2
Keywords
KLF5; Hypoxia; DDP resistance; Glycolysis; The PI3K/Akt/mTOR pathway; NSCLC
Categories
Funding
- Key Project of Hanan Educational committee [17A180019]
- Fundamental Research Funds for the Henan Provincial Colleges and Universities in Henan University of Technology
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Background: Hypoxia-mediated chemoresistance has been regarded as an important obstacle in the development of cancer treatment. Knockdown of kruppel-like factor 5 (KLF5) was reported to inhibit hypoxia-induced cell survival and promote cell apoptosis in non-small cell lung cancer (NSCLC) cells via direct regulation of hypoxia inducible factor-1 alpha (HIF-1 alpha) expression. However, the roles of KLF5 in the development of hypoxia-induced cisplatin (DDP) resistance and its underlying mechanism in NSCLC cells remain to be further elucidated. Methods: Western blot was performed to determine the protein levels of KLF5, P-glycoprotein (P-gp) and HIF-1 alpha in treated NSCLC cells. Cell survival was examined by MTT assay. The effect of KLF5 knockdown on hypoxia-induced glycolysis was assessed by measuring glucose consumption and lactate production. The effect of KLF5 knockdown on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway was analyzed by western blot. Results: Hypoxia upregulated the expression of KLF5 in NSCLC cells. KLF5 knockdown suppressed hypoxia-induced DDP resistance in NSCLC cells, as demonstrated by the increased cytotoxic effects of DDP and reduced P-gp expression in NSCLC cells in hypoxia. Moreover, KLF5 knockdown inhibited hypoxia-induced HIF-1 alpha expression and glycolysis, and KLF5 knockdown suppressed hypoxia-induced DDP resistance by inhibiting HIF-1 alpha-dependent glycolysis in NSCLC cells. Furthermore, KLF5 knockdown suppressed hypoxia-induced activation of the PI3K/Akt/mTOR pathway in NSCLC cells and KLF5 overexpression promoted hypoxia-induced DDP resistance in NSCLC cells through activation of the PI3K/Akt/mTOR pathway. Conclusions: KLF5 knockdown could suppress hypoxia-induced DDP resistance, and its mechanism may be due to the inhibition of HIF-1-dependent glycolysis via inactivation of the PI3K/Akt/mTOR pathway.
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