Drug resistance and cancer stem cells: the shared but distinct roles of hypoxia-inducible factors HIF1 alpha and HIF2 alpha

作者：Schoning Jennifer Petra; Monteiro Michael; Gu Wenyi

来源：CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, 2017, 44(2): 153-161.

DOI：10.1111/1440-1681.12693

• cancer stem cells
• drug resistance
• drug transporters
• HIF1 alpha
• HIF2 alpha
• hypoxia
• hypoxia-inducible factors
• PI3K/AKT signalling pathway
• quiescence

Chemotherapy resistance is a major contributor to poor treatment responses and tumour relapse, the development of which has been strongly linked to the action of cancer stem cells (CSCs). Mounting evidence suggests that CSCs are reliant on low oxygen conditions and hypoxia-inducible factors 1 alpha and 2 alpha (HIF1 alpha and HIF2 alpha) to maintain their stem cell features. Research in the last decade has begun to clarify the functional differences between the two HIF alpha subtypes (HIF alpha s). Here, we review and discuss these differences in relation to CSC-associated drug resistance. Both HIFas contribute to CSC survival but play different roles - HIF1 alpha being more responsible for survival functions and HIF2 alpha for stemness traits such as self-renewal - and are sensitive to different degrees of hypoxia. Failure to account for physiologically relevant oxygen concentrations in many studies may influence the current understanding of the roles of HIF alpha s. We also discuss how hypoxia and HIF alpha s contribute to CSC drug resistance via promotion of ABC drug transporters Breast cancer resistance protein (BCRP), MDR1, and MRP1 and through maintenance of quiescence. Additionally, we explore the PI3K/AKT cell survival pathway that may support refractory cancer by promoting CSCs and activating both HIF1 alpha and HIF2 alpha. Accordingly, HIF1 alpha and HIF2 alpha inhibition, potentially via PI3K/AKT inhibitors, could reduce chemotherapy resistance and prevent cancer relapse.

• 出版日期2017-2