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

in Molecular carcinogenesis by Ako Yokoi, Daigo Yoshimori, Yasuko Oguri, Miki Hashimura, Makoto Saegusa

TLDR

  • A novel ALK transcript is overexpressed in ovarian high-grade serous carcinoma, sensitizing cells to apoptosis through PARP1 association.
  • ALK-mediated apoptosis is independent of mitochondrion-driven cell death.

Abstract

The current study aims to delineate the role of a novel anaplastic lymphoma kinase (ALK) transcript, ALK, in ovarian high-grade serous carcinoma (HGSC). Overexpressed ALKexhibited both cytoplasmic and nuclear localization in HGSC cells, whereas full-length ALK was predominantly cytoplasmic. ALKinteracts with the DNA repair protein, poly (ADP ribose) polymer 1 (PARP1), and cells stably overexpressing ALK(OE- ALK) 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-ALKcells, despite the increase in apoptosis, suggesting that ALK-mediated apoptosis is independent of mitochondrion-driven cell death. OE-ALKdecreased 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 ALKsensitizes HGSC cells to apoptosis (probably though an association with PARP1) but this may have a relatively minor impact on tumor progression.

Overview

  • The study investigates the role of a novel anaplastic lymphoma kinase (ALK) transcript in ovarian high-grade serous carcinoma (HGSC).
  • ALK overexpression exhibits both cytoplasmic and nuclear localization in HGSC cells, with full-length ALK being mostly cytoplasmic.
  • The study aims to determine the impact of ALK on HGSC cells and its potential therapeutic applications.

Comparative Analysis & Findings

  • ALK interacts with the DNA repair protein, poly (ADP ribose) polymer 1 (PARP1), and cells stably overexpressing ALK (OE-ALK) are more sensitive to cisplatin-induced apoptosis.
  • Cleaved PARP1 levels are higher in HGSC tissue samples with nuclear ALK immunoreactivity.
  • OE-ALK cells exhibit increased apoptosis, but the ratio of antiapoptotic BCL2 relative to proapoptotic BAX is significantly increased, suggesting ALK-mediated apoptosis is independent of mitochondrion-driven cell death.

Implications and Future Directions

  • ALK may sensitize HGSC cells to apoptosis through its association with PARP1, potentially providing a therapeutic target.
  • Further research is needed to explore the potential impact of ALK on tumor progression and to identify potential combination therapies.
  • The study highlights the need for a deeper understanding of the molecular mechanisms underlying HGSC and the development of effective treatments.
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