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

Abstract

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-1α (HIF-1α) 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-1α 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-1α through the ROS-mediated, extracellular signal-regulated kinase and Akt pathway. These findings provide direct evidence that the RASAL1/HIF-1α 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.

RASAL1 and ROS1 Gene Variants in Hereditary Breast Cancer

“…In particular, RASAL1 overexpression resulted significantly correlated with a worse outcome (increased death) in endometrial cancer ( Figure S1D ), whereas NPL overexpression was correlated to a worse outcome in liver and renal cancers ( Figure S1E ). However, in other studies RASAL1 was found significantly downregulated in cancer [ 19 , 20 ], whereas its overexpression blocked cancer progression [ 21 ].…”

“…POLN encodes for the DNA Polymerase nu involved in cross-link repair, homologous recombination and binding to BRCA1 [ 36 ]. ROS1 and RASAL1 are two genes with established roles in tumor development and progression in different types of cancer [ 21 , 24 , 25 , 37 , 38 ].…”

“…Acting as a suppressor of RAS function, the protein enhances the intrinsic GTPase activity of RAS proteins resulting in the inactive GDP-bound form of RAS, thereby controlling cellular proliferation and differentiation [ 19 , 20 ]. Recent data have shown that exogenous expression of RASAL1 in MCF-7 and MDA-MB-231 sensitized the response to hypoxia treatments, associated with its ability to directly reduce HIF-1α (Hypoxia-inducible factor 1-alpha) expression, inhibiting migration and decreasing the accumulation of reactive oxygen species [ 21 ]. Conversely, RASAL1 knockdown reversed the cellular response to hypoxia [ 21 ].…”

“…Recent data have shown that exogenous expression of RASAL1 in MCF-7 and MDA-MB-231 sensitized the response to hypoxia treatments, associated with its ability to directly reduce HIF-1α (Hypoxia-inducible factor 1-alpha) expression, inhibiting migration and decreasing the accumulation of reactive oxygen species [ 21 ]. Conversely, RASAL1 knockdown reversed the cellular response to hypoxia [ 21 ]. Somatic driver gene point mutations in RASAL1 in follicular thyroid cancer have also been reported [ 24 ].…”

The role of hypoxia-induced factor 1�� in breast cancer

“…The RAS protein activator 1 (RASAL1) protein is known to be involved in the progression of hypoxia resistance in breast cancer cells. The increase of intracellular Ca 2+ ions stimulates RASAL1, which leads to attenuation of RAS activation and mitogen-activated protein kinase (MAPK) activity and contributes to tumor progression through weakened anti-RAS activity [12] . In periods of hypoxia, reactive oxygen species accumulation activates PI3k/Akt (Protein-kinase B) and MAPK/ERK (extracellular signal-regulated kinase) pathways, essential for the maintenance of carcinogenesis, tumor angiogenesis and activation of HIF-1α.…”