Hypoxia regulates ABCG₂activity through the activivation of ERK1/2/HIF-1α and contributes to chemoresistance in pancreatic cancer cells

Abstract

Pancreatic cancer is a drug resistant hypovascular tumor. Although there are many studies on the mechanism of chemoresistance in pancreatic cancers, studies on the relationship between ABCG2 and chemoresistance during hypoxia of pancreatic cancer are rare. Hypoxia-inducible factor-1 (HIF-1a) is a master regulator of the transcriptional response to oxygen deprivation in cancer cells. The aim of this study was to examine the role of ABCG 2 and HIF-1a in mediating chemoresistance during hypoxia in pancreatic cancer. In this study, we detected the expression levels of ABCG 2 , ERK/phosphorylated-ERK (p-ERK) and HIF-1a by immunohistochemistry in fresh pancreatic cancer and paracarcinoma tissues obtained from 25 patients. The mechanism by which p-ERK1/2 and HIF-1a affect ABCG 2 s expression was analyzed in the hypoxic cultured human pancreatic cancer cell line Capan-2. ABCG2-mediatedregulation of gemcitabine response under hypoxic conditions in pancreatic cancer cells was observed. It was found that ABCG 2 , ERK/p-ERK and HIF-1a were overexpressed in cancer tissues. ABCG2, HIF-1a and p-ERK levels were demonstrated to be high during hypoxic conditions in pancreatic cancer cells. Hypoxia induced phosphorylation of ERK1/2 to activate HIF-1a and contribute the ABCG 2 expression and mediated gemcitabine chemoresistance in pancreatic cancer cells. Hypoxic conditions induced HIF-1a binding to target gene sequences in the ABCG 2 promoter, resulting in increased transcription in pancreatic cancer cells. We demonstrated that hypoxia-induced chemoresistance is due to the regulation of ABCG 2 through the activation of ERK1/2/HIF-1a. ABCG 2 could serve as a predictor of gemcitabine response and, potentially, as a chemotherapeutic target in pancreatic cancer. Inhibition of ERK1/2 and HIF-1acould result in increased gemcitabine sensitization in pancreatic cancer with highly expressed ABCG 2 cell member protein.

Hippo pathway mediates resistance to cytotoxic drugs

“…S8) (60,61). In particular, a recent study has shown that ABCG2 expression regulates gemcitabine response in pancreatic cancer (62). There is some specificity because we found no correlation between overall survival and the levels of Hippo-independent drug transporters in pancreatic cancers (SI Appendix, Fig.…”

ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches

“…A large number of cis-regulatory regions have been identified in or near the promoter region of ABCG2 (reviewed in39). Hypoxia-inducible factor-1 (HIF-1α) stabilizes under hypoxic conditions and has been found to bind to a hypoxia-responsive element in the ABCG2 promoter and increase expression 40,41. Upstream of HIF-1α, signaling via phosphatase and tensin homolog (PTEN), phosphoinositide 3-kinase (PI3K) and protein B kinase (Akt) regulates ABCG2 expression on the cell membrane 42–45.…”

Hypoxia alters the release and size distribution of extracellular vesicles in pancreatic cancer cells to support their adaptive survival

“…8 As a result, PC cells encounter moderate to extreme hypoxia during the course of their progression, which alter their cellular and behavioral properties. 3,10,11 However, underlying mechanisms remain poorly understood. 3,10,11 However, underlying mechanisms remain poorly understood.…”