BCL-XL directly modulates RAS signalling to favour cancer cell stemness. Issue 1 (December 2017)

• Record Type: Journal Article
• Authors: Carné Trécesson, Sophie; Souazé, Frédérique; Basseville, Agnès; Bernard, Anne-Charlotte; Pécot, Jessie; Lopez, Jonathan; Bessou, Margaux; Sarosiek, Kristopher; Letai, Anthony; Barillé-Nion, Sophie; Valo, Isabelle; Coqueret, Olivier; Guette, Catherine; Campone, Mario; Gautier, Fabien; Juin, Philippe Paul
• Is Part Of: Nature communications. Volume 8:Issue 1(2017)
• Page Start: 1
• Page End: 11
• Publication Date: 2017-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-017-01079-1
• Languages: English
• ISSNs: 2041-1723

Abstract

Abstract In tumours, accumulation of chemoresistant cells that express high levels of anti-apoptotic proteins such as BCL-XL is thought to result from the counter selection of sensitive, low expresser clones during progression and/or initial treatment. We herein show that BCL-XL expression is selectively advantageous to cancer cell populations even in the absence of pro-apoptotic pressure. In transformed human mammary epithelial cells BCL-XL favours full activation of signalling downstream of constitutively active RAS with which it interacts in a BH4-dependent manner. Comparative proteomic analysis and functional assays indicate that this is critical for RAS-induced expression of stemness regulators and maintenance of a cancer initiating cell (CIC) phenotype. Resistant cancer cells thus arise from a positive selection driven by BCL-XL modulation of RAS-induced self-renewal, and during which apoptotic resistance is not necessarily the directly selected trait. BCL-XL provides a survival advantage to cancer cells even in the absence of apoptotic pressures. In this study, the authors show that BCL-XL interacts with RAS in a BH4-dependent manner and regulates RAS-mediated activation of pathways involved in the stemness feature of breast cancer cells.