RBMS2 Chemosensitizes Breast Cancer Cells to Doxorubicin by Regulating BMF Expression

Abstract

Chemoresistance is closely related to the therapeutic effect and prognosis in breast cancer patients. Increasing evidences demonstrated that RNA binding proteins (RBPs) have notable roles in regulating cancer cell proliferation, metastasis and chemotherapeutic sensitivity. RNA binding motif single stranded interacting protein 2 (RBMS2), an RBP, has been considered to be a tumor suppressor in several cancers. However, its role of doxorubicin sensitivity in breast cancer patients has not yet been fully revealed.Here, we performed doxorubicin cytotoxicity assay, flow cytometry and mouse xenograft model to examine the influence of RBMS2 on doxorubicin sensitization in vitro and in vivo. RIP assay and dual-luciferase reporter assay were performed to explore the relationship between RBMS2 and BMF. Our data demonstrated that upregulation of RBMS2 in breast cancer cells could enhance sensitivity to doxorubicin and promote apoptosis in the presence of doxorubicin, while inhibition of RBMS2 showed an opposite trend. Moreover, this chemosensitizing effect of RBMS2 could be reversed by the inhibition of Bcl-2 modifying factor (BMF). RBMS2 positively regulated BMF expression and increased BMF-induced expression of (cleaved) caspase 3, (cleaved) caspase 9 and poly (ADP-Ribose) polymerase (PARP). These results uncovered a novel mechanism for RBMS2 in the sensibilization of doxorubicin, suggesting that RBMS2 may act as a potential therapeutic target for drug-resistant breast cancer.

LncRNA RP11-521C20.3 Inhibits Cigarette Smoke Extract-Induced Apoptosis in A549 Cells by Targeting BMF Signaling

“… 40 In the presence of Adriamycin, upregulated RBMS2 in breast cancer cells promotes BMF expression and increases expression of cleaved caspase-3, cleaved caspase-9, and poly ADP-ribose polymerase to exacerbate apoptosis. 43 In addition, knockdown of Eomes in human colon cancer cells increases BMF expression, which is accompanied by increased levels of cleaved caspase-3 and cleaved caspase-7, and decreased expression of survivin, leading to apoptosis. 44 In fact, our research showed that overexpression of BMF in CSE-treated A549 cells increased the expression of pro-apoptotic proteins (p53, caspase-3, and caspase-7) and inhibited the expression of anti-apoptotic proteins (Bcl-2 and survivin) to exacerbate apoptosis.…”

The Clinical and Cellular Impact of RBMS2 on the Progression and Prognosis of Kidney Renal Clear Cell Carcinoma

“…These findings highlight the therapeutic potential of RBMS2 in ccRCC. Indeed, RBMS2 was reported to chemosensitize breast cancer cells to doxorubicin, implying its therapeutic potential [ 3 ].…”

“…Investigations into different types of cancers such as lung cancer, gastric cancer, and hepatocellular carcinoma have reported a downregulation of RBMS2. This diminished expression of RBMS2 is seen to contribute to the initiation and progression of these cancers, thereby establishing a link between RBMS2 downregulation and oncogenesis [ 3 ]. However, the role of RBMS2 in kidney renal clear cell carcinoma (ccRCC), which is the most prevalent subtype of kidney cancer, has not been thoroughly explored.…”

Novel roles of RNA-binding proteins in drug resistance of breast cancer: from molecular biology to targeting therapeutics

“…Upregulation of RNA binding motif single stranded interacting protein 2 enhances the sensitivity of BC cells to doxorubicin, while inhibition of this RBP has an opposite trend. Motif single stranded interacting protein 2 positively regulates the expression of Bcl-2 modifier and increases the expression of cleaved caspase 3, cleaved caspase 9 and poly (ADP-ribose) polymerase which in turn contributes to doxorubicin sensitivity [64]. Epirubicin is another anthracycline agent widely used for BC treatment.…”