https://researchopenworld.com/ribosomal-s6-kinase-2-promotes-survival-of-triple-negative-breast-cancer-cells-to-apoptotic-stimuli/#

Abstract

Triple-negative breast cancers (TNBC) lack estrogen receptor (ER), progesterone receptor and epidermal growth factor receptor HER2 and share many features of basal-like breast cancer (BLBC). Therefore, these patients have to rely on chemotherapy. The mechanistic target of rapamycin complex 1 (mTORC1) as well as its downstream targets p70 S6 kinase (S6K1) and S6K2 have been implicated in breast cancer. The 40S ribosomal protein S6 kinase 2 (S6K2) has been associated with endocrine resistance. We have previously shown that S6K2 protects against apoptotic cell death in ER-positive breast cancer cells. In the present study, we investigated if S6K2 could serve as a potential target for TNBC. Our analysis of TCGA dataset as well as immunohistochemistry of patient samples revealed that S6K2 is overexpressed not only in ER-positive but also in TN breast tumors compared to normal breast tissues. Silencing of S6K2 by siRNA enhanced sensitivity of BLBC MCF10CA1d cells to chemotherapeutic drugs cisplatin and doxorubicin. S6K2 knockdown also increased sensitivity of BLBC MCF10CA1a and TNBC HCC1395 cells to TRAIL. While S6K2 knockdown alone had little effect on apoptosis, it enhanced TRAIL-induced apoptosis as judged by the increase in caspase-3 activity, PARP cleavage and annexin V/PI staining. Overexpression of constitutively-active S6K2 construct in MDA-MB-231 cells protected against TRAIL-induced apoptosis. These results suggest that S6K2 also promotes survival of TNBC. Therefore, targeting S6K2 in combination with chemotherapeutic agents could improve therapy of TNBC.