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

Abstract

Blocking dephosphorylation of eukaryotic translation initiation factor 2α (eIF2α) is reported to alter proliferation and differentiation of various cells. Using salubrinal and guanabenz as an inhibitory agent of dephosphorylation of eIF2α, we addressed a question whether an elevated level of phosphorylated eIF2α 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 eIF2α revealed that eIF2α is involved in the reduction in invasion and motility. Furthermore, salubrinal-driven inactivation of Rac1 was suppressed in the cells treated with eIF2α 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 eIF2α-mediated Rac1 pathway. Since salubrinal and guanabenz are known to inhibit bone resorption, this study provides a potential use of eIF2α-mediated Rac1 regulation in suppressing the growth and metastasis of breast cancer.

Inhibitory Effects of Dopamine Receptor D1 Agonist on Mammary Tumor and Bone Metastasis

“…Rac1 GTPase regulates various cellular processes, such as cell cycle, motility, invasion, and cell-cell adhesion16, and plays a critical role in the development and metastasis of various cancers, including breast cancer17. Salubrinal is also reported to inhibit Rac1 activity via eIF2α-mediated signaling18. In SW1353 chondrosarcoma cells, it is reported that Rac1 GTPase was suppressed by the elevation of p-eIF2α19.…”

The role of TGF-β and its crosstalk with RAC1/RAC1b signaling in breast and pancreas carcinoma

“…In addition, MST3 promotes proliferation and tumorigenicity through the VAV2/RAC1 signal axis in breast cancer [64] and RASAL2 activates RAC1 to promote triple-negative breast cancer progression [65]. Loss of the E3 ubiquitin ligase HACE1 results in enhanced RAC1 signaling contributing to breast cancer progression [66] while eIF2α-mediated downregulation of RAC1 signaling attenuates malignant phenotypes of breast cancer cells [67]. In PDAC progression the RAC1 GEF VAV1 has been shown to possess a role by acting synergistically with the EGFR to stimulate pancreatic tumor cell proliferation [68].…”

Reduction in Migratory Phenotype in a Metastasized Breast Cancer Cell Line via Downregulation of S100A4 and GRM3

“…Three in vitro assays were employed to characterize phenotypic differences in migratory and invasive behaviors, including a 2-dimensional motility assay 13 , a 3-dimensional invasion assay 14 , and a 3-dimensional spheroid assay 15 . Furthermore, a microfluidic assay was employed to characterize cellular motility in the presence and absence of Paclitaxel 16–18 .…”