RAS protein activator-like 1 is functionally involved in hypoxia resistance in breast cancer cells by targeting hypoxia inducible factor-1 alpha

摘要

RAS protein activator-like 1 (RASAL1) is a member of the RAS GTPase-activating protein family, and previous studies indicate that RASAL1 is involved in the progression of hypoxia resistance in breast cancer cells. In the present study, increased levels of hypoxia inducible factor-1 alpha (HIF-1 alpha) were observed to be accompanied with increased expression of RASAL1 in the breast cancer cell lines MCF-7 and MDA-MB-231 cells under hypoxia. Based on this, it was postulated that RASAL1 may serve a functional role in the development of hypoxia resistant in breast cancer cells. In the present study it was demonstrated that: i) Exogenous expression of RASAL1 in MCF-7 and MDA-MB-231 sensitized its reaction to the. treatment of hypoxia, which is associated with its ability to directly reduce HIF-la expression, inhibit migration activity and decrease the accumulation of reactive oxygen species (ROS); ii) knockdown of RASAL1 reversed its reaction to treatment with hypoxia; iii) RASAL1 directly regulated the expression of HIF-la through the ROS-mediated, extracellular signal-regulated kinase and Akt pathway. These findings provide direct evidence that the RASALl/HIF-1 alpha axis may serve an essential role in the hypoxia resistance of breast cancer cells, suggesting that this signaling cohort may serve as a novel therapeutic target for the treatment of breast cancer.