IFI6 Downregulation Reverses Oxaliplatin Resistance of Colorectal Cancer Cells by Activating the ROS-Induced p38MAPK Signaling Pathway

Abstract

Oxaliplatin (OXA) is a usual chemotherapeutic agent applied in the colorectal cancer (CRC) clinical treatment. Interferon-alpha inducible protein 6 (IFI6) has been proved to promote proliferation and suppress apoptosis in several tumor cells, while the impacts of IFI6 on OXA resistance in CRC still need exploration. HCT116 and SW620 cells were used as the parental to obtain OXA-resistant cells. The influence of IFI6 on OXA sensitivity, cell proliferation and apoptosis were evaluated by overexpression or knockdown IFI6 in cells. In this work, we found that the level of IFI6 was significantly enhanced in HCT116/OXA and SW620/OXA cells as compared to the parental cells. Overexpression of IFI6 decreased the sensitivity of HCT116 and SW620 cells to OXA. However, knockdown of IFI6 enhanced the sensitivity of HCT116/OXA and SW620/OXA cells to OXA. And upregulated IFI6 promoted the proliferation and repressed apoptosis in HCT116 cells, while suppressed IFI6 markedly reduced proliferation and increased apoptosis in HCT116/OXA cells. Additionally, IFI6 suppressed the phosphorylation level of p38, and silenced IFI6 enhanced it. The addition of the p38 kinase inhibitor, SB203580, alleviated the decreased cell proliferation and increased apoptosis in HCT116/OXA cells. Suppressed IFI6 enhanced the reactive oxygen species (ROS) level in HCT116/OXA cells, and blockade of ROS with N-acetyl-L-cysteine (NAC) decreased the enhancement level of ROS and the phosphorylation level of the p38, which was induced by IFI6 down-regulation. We, therefore, implied that suppressed IFI6 reverses OXA-resistance of CRC cells via promoting the ROS-induced p38 mitogen-activated protein kinase (MAPK) signaling pathway. Key words interferon-alpha inducible protein 6, oxaliplatin, colorectal cancer, reactive oxygen species, p38 mitogen-activated protein kinase (MAPK)

FABP4 Regulates Cell Proliferation, Stemness, Apoptosis, and Glycolysis in Colorectal Cancer via Modulating ROS/ERK/mTOR Pathway

“…All cell lines underwent stringent mycoplasma testing and STR validation procedures. As a reactive oxygen species (ROS) scavenger, N-acetyl-L-cysteine (NAC; 2 mM, MedChem-Express, Shanghai, China) was employed to treat the HT29 and SW480 cells [37].…”