Autophagy promotes paclitaxel resistance of cervical cancer cells: involvement of Warburg effect activated hypoxia-induced factor 1-α-mediated signaling

Abstract

Paclitaxel is one of the most effective chemotherapy drugs for advanced cervical cancer. However, acquired resistance of paclitaxel represents a major barrier to successful anticancer treatment. In this study, paclitaxel-resistant HeLa sublines (HeLa-R cell lines) were established by continuous exposure and increased autophagy level was observed in HeLa-R cells. 3-Methyladenine or ATG7 siRNA, autophagy inhibitors, could restore sensitivity of HeLa-R cells to paclitaxel compared with parental HeLa cells. To determine the underlying molecular mechanism, differentially expressed proteins between HeLa and HeLa-R cells were identified by two-dimensional gel electrophoresis coupled with electrospray ionization quadrupole time-of-flight MS/MS. We found glycolysis-associated proteins were upregulated in HeLa-R cell lines. Inhibition of glycolysis by 2-deoxy-D-glucose or koningic acid could decrease autophagy and enhance sensitivity of HeLa-R cells to paclitaxel. Moreover, glycolysis could activate HIF1-α. Downregulation of HIF1-α by specific siRNA could decrease autophagy and resensitize HeLa-R cells to paclitaxel. Taken together, a possible Warburg effect activated HIF1-α-mediated signaling-induced autophagic pathway is proposed, which may provide new insight into paclitaxel chemoresistance.

Vascular ageing and endothelial cell senescence: Molecular mechanisms of physiology and diseases

“…Hypoxia HIF activation determines a shift from oxidative to glycolytic metabolism abrogating reliance on oxygen supply, mitochondria respiration and facilitating redox homeostasis (AbuRemaileh and Aqeilan, 2014;Hu et al, 2014;Hwang and Lee, 2011;Peng et al, 2014;Semenza, 2011b;Wu et al, 2015). In particular in hypoxia, HIF-1 reciprocally regulates COX4 subunit expression by activating transcription of the genes encoding COX4i2 and the mitochondrial protease required for COX4i1 degradation .…”

TAp73 transcriptionally represses BNIP3 expression

“…93 BNIP3 is also known to lead to autophagy, which may promote both tumor suppression and tumor growth, and the implication of autophagy in cancer progression can be different. [94][95][96][97][98][99] BNIP3 has also been shown to act as a transcriptional factor: if it translocates to nucleus, it suppresses Apoptosis-Inducing Factor expression, preventing cell death, thus showing tumorigenic function. 85 Our bioinformatics analysis would suggest an oncogenic function for BNIP3.…”

Immunomodulatory and antimicrobial activity of a polyherbal composition, Panchatulasi drops, derived from essential oils of five species of basil

“…Both drugs have been suggested as anti-inflammation agents, but are associated with adverse effects. Paclitaxel is associated with anaphylaxis, severe hypersensitivity reactions and resistance at high doses (Peng et al, 2014). Other side effects include hair loss, low blood count, nail disorders, diarrhea and peripheral neuropathy.…”