PLK1 and AURKB phosphorylate survivin differentially to affect proliferation in racially distinct triple-negative breast cancer

• Type of Material: Article
• Authors: Chakravarthy Garlapati, Alkermes Inc; Shriya Joshi, Georgia State University; Shristi Bhattarai, Georgia State University; Jayashree Krishnamurthy, Georgia State University; Ravi Chakra Turaga, Caris Life Sciences; Thi Nguyen, Emory University; Xiaoxian Li, Emory University; Ritu Aneja, Georgia State University
• Language: English
• Date: 2023-01-10
• Publisher: SPRINGERNATURE
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41419-022-05539-5
• Title of Journal or Parent Work: CELL DEATH & DISEASE
• Volume: 14
• Issue: 1
• Start Page: 12
• End Page: 12
• Grant/Funding Information: This work was supported by a grant from the National Cancer Institute (R01CA239120) to R.A.
• Keywords: POSTTRANSLATIONAL MODIFICATIONS; Life Sciences & Biomedicine; EXPRESSION; CELLS; Science & Technology; APOPTOSIS; MONOETHANOLAMINE; Cell Biology; INHIBITION
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Protein diversity due to alternative mRNA splicing or post-translational modifications (PTMs) plays a vital role in various cellular functions. The mitotic kinases polo-like kinase 1 (PLK1) and Aurora B (AURKB) phosphorylate survivin, an inhibitor of apoptosis (IAP) family member, thereby regulating cell proliferation. PLK1, AURKB, and survivin are overexpressed in triple-negative breast cancer (TNBC), an aggressive breast cancer subtype. TNBC is associated with high proliferative capacity, high rates of distant metastasis, and treatment resistance. The proliferation-promoting protein survivin and its activating kinases, PLK1 and AURKB, are overexpressed in TNBC. In this study, we investigated the role of survivin phosphorylation in racial disparities in TNBC cell proliferation. Analysis of TCGA TNBC data revealed higher expression levels of PLK1 (P = 0.026) and AURKB (P = 0.045) in African Americans (AAs; n = 41) than in European Americans (EAs; n = 86). In contrast, no significant racial differences in survivin mRNA or protein levels were observed. AA TNBC cells exhibited higher p-survivin levels than EA TNBC cells. Survivin silencing using small interfering RNAs significantly attenuated cell proliferation and cell cycle progression in AA TNBC cells, but not in EA TNBC cells. In addition, PLK1 and AURKB inhibition with volasertib and barasertib significantly inhibited the growth of AA TNBC xenografts, but not of EA TNBC tumors. These data suggest that inhibition of PLK1 and AURKB suppresses cell proliferation and tumor growth, specifically in AA TNBC. These findings suggest that targeting survivin phosphorylation may be a viable therapeutic option for AA patients with TNBC. [Figure not available: see fulltext.]