A Transcriptional Variant of Anaplastic Lymphoma Kinase Promotes Apoptosis in Ovarian High-Grade Serous Carcinoma.

Abstract

The current study aims to delineate the role of a novel anaplastic lymphoma kinase (ALK) transcript, ALK^ATI, in ovarian high-grade serous carcinoma (HGSC). Overexpressed ALK^ATI exhibited both cytoplasmic and nuclear localization in HGSC cells, whereas full-length ALK was predominantly cytoplasmic. ALK^ATI interacts with the DNA repair protein, poly (ADP ribose) polymer 1 (PARP1), and cells stably overexpressing ALK^ATI (OE- ALK^ATI) were more sensitive to cisplatin-induced apoptosis. Consistent with this, cleaved PARP1 levels were higher in HGSC tissue samples in areas with nuclear ALK immunoreactivity. The ratio of antiapoptotic BCL2 relative to proapoptotic BAX was significantly increased in OE-ALK^ATI cells, despite the increase in apoptosis, suggesting that ALK^ATI-mediated apoptosis is independent of mitochondrion-driven cell death. OE-ALK^ATI decreased epithelial-mesenchymal transition/cancer stem cell properties but did not alter proliferation rates, and nuclear ALK immunopositivity was not associated with clinicopathological factors or prognosis in HGSC. Together, our observations suggest that ALK^ATI sensitizes HGSC cells to apoptosis (probably though an association with PARP1) but this may have a relatively minor impact on tumor progression.