Attenuation of malignant phenotypes of breast cancer cells through eIF2α-mediated downregulation of Rac1 signaling

Blocking dephosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2 alpha) is reported to alter proliferation and differentiation of various cells. Using salubrinal and guanabenz as an inhibitory agent of dephosphorylation of eIF2 alpha, we addressed a question whether an elevated level of phosphorylated eIF2 alpha attenuates malignant phenotypes of triple negative breast cancer cells (TNBCs) that lack estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2. We determined effects of salubrinal and guanabenz on in vitro phenotype of 4T1 mammary tumor cells and MDA-MB-231 human breast cancer cells and evaluated their effects on in vivo tumor growth using BALB/c mice injected with 4T1 cells. The results revealed that these agents block the proliferation and survival of 4T1 and MDA-MB-231 cells, as well as their invasion and motility. Silencing eIF2 alpha revealed that eIF2 alpha is involved in the reduction in invasion and motility. Furthermore, salubrinal-driven inactivation of Rac1 was suppressed in the cells treated with eIF2 alpha siRNA, and treatment with Rac1 siRNA reduced cell invasion and motility. In vivo assay revealed that subcutaneous administration of salubrinal reduced the volume and weight of tumors induced by 4T1 cells. Collectively, the results indicate that these agents can attenuate malignant phenotype and tumor growth of breast cancer cells through the eIF2 alpha-mediated Rac1 pathway. Since salubrinal and guanabenz are known to inhibit bone resorption, this study provides a potential use of eIF2 alpha-mediated Rac1 regulation in suppressing the growth and metastasis of breast cancer.