Hypoxic Hepatocellular Carcinoma Cells Acquire Arsenic Trioxide Resistance by Upregulating HIF-1α Expression

• Published in: Digestive diseases and sciences Vol. 67; no. 8; pp. 3806 - 3816
• Main Authors: Chen, Yaoting, Li, Huiqing, Chen, Dong, Jiang, Xiongying, Wang, Weidong, Li, Dan, Shan, Hong
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.08.2022; Springer Nature B.V
• Subjects: Angiogenesis; Apoptosis; Arsenic; Biochemistry; Gastroenterology; Glycoproteins; Hepatology; Hypoxia; Liver cancer; Medicine; Medicine & Public Health; Oncology; Original Article; Protein expression; Transplant Surgery; Hepatocellular carcinoma; Arsenic trioxide; HIF-1α; Drug resistance; Targeted therapy
• ISSN: 0163-2116; 1573-2568
• DOI: 10.1007/s10620-021-07202-z

Background Although arsenic trioxide (ATO) is used in the treatment of advanced hepatocellular carcinoma (HCC) in clinical trials, it is not satisfactory in terms of improving HCC patients’ overall survival. Intratumoral hypoxia and overexpression of hypoxia-inducible factor-1α (HIF-1α) may result in ATO resistance and tumor progression. Aims We investigated the mechanisms involving HIF-1α expression and acquired ATO chemoresistance in HCC cells and mice. Methods The therapeutic effects of ATO in normoxic and hypoxic HCC cells were assessed using cell viability and apoptosis assays in vitro and a xenograft model in vivo. mRNA and protein expression of HIF-1α, P-glycoprotein, and VEGF were measured by qRT-PCR and western blotting. HIF-1α inhibition was performed to investigate the mechanism of ATO resistance. VEGF secretion was tested using ELISA and tube formation assays. Results Compared to normoxic cells, hypoxic HCC cells were more resistant to ATO, with higher IC 50 values and less apoptosis, and upregulated HIF-1α protein expression, accompanied with the enhancement of P-glycoprotein and VEGF synthesis after ATO treatment. VEGF secretion was elevated in the supernatant of ATO-treated HCC cells, and this change can potentiate angiogenesis in vitro. HIF-1α inhibition attenuated ATO resistance and angiogenesis and promoted the anticancer effects of ATO both in vitro and in vivo by downregulating therapy-induced P-glycoprotein and VEGF overexpression. Conclusions Hypoxic HCC cells acquire ATO resistance by upregulating HIF-1α levels; thus, combining ATO with a HIF-1α-targeting agent may lead to enhanced antitumor effects in HCC.