Chemoresistance is a major reason for treatment failure and results in poor prognosis in patients with advanced colorectal cancer (CRC). Hypoxia-inducible factor-1 (HIF1-α) is a regulator of the transcriptional response to oxygen deprivation in cancer cells and activates the transcription of genes that are involved in angiogenesis, cell survival and invasion. However, the effect of HIF1-α activation on oxaliplatin resistance in CRC is unclear. This study aimed to investigate the effects and potential mechanism of HIF1-α on oxaliplatin resistance in CRC.
Oxaliplatin-resistant cells were generated from HCT116 cells. Cell Counting Kit-8, flow cytometry, Transwell assay were used to compare the characteristics of oxaliplatin resistant HCT116 (HCT116_OxR) cells and the corresponding parental HCT116 cells. The expression of HIF1-α, extracellular signal-related kinase (ERK), and transforming growth factor β (TGFβ) were confirmed by RT-PCR and western blotting in HCT116_OxR and HCT116 cells. Next, we evaluated the combination efficacy of inhibitors of HIF1-α (YC-1), ERK (Ravoxertinib), and TGFβ1 (SB431542) with oxaliplatin by in vitro and in vivo experiments.
We found that cell viability of HCT116_OxR was higher than that in parental cells in the presence of oxaliplatin. The relative expression of HIF1-α was significantly increased in HCT116_OxR cells compared with the parental HCT116 cells. Downregulation of HIF1-α in HCT116_OxR cells increased oxaliplatin sensitivity, and diminished cell survival and invasion. Significantly, ERK signaling in HCT116_OxR cells is dependent on TGFβ1, promoting oxaliplatin resistance by activating HIF1-α. Inhibition of ERK by Ravoxertinib or TGFβ1 by SB431542 efficiently overcame oxaliplatin resistance in vitro and in vivo.
HIF1-α activation is regulated by TGFβ1/ERK axis in HCT116_OxR cells. Hence, HIF1-α, ERK, and TGFβ1 are potential therapeutic targets for overcoming oxaliplatin resistance in patients with CRC.
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All authors have declared no conflicts of interest.