A genome-wide loss-of-function screen identifies SLC26A2 as a novel mediator of TRAIL resistance

Lina Y. Dimberg, Christina G. Towers, Kian Behbakht, Taylor J. Hotz, Jihye Kim, Susan Fosmire, Christopher C. Porter, Aik-Choon Tan, Andrew Thorburn, Heide L. Ford

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

TRAIL is a potent death-inducing ligand that mediates apoptosis through the extrinsic pathway and serves as an important endogenous tumor suppressor mechanism. Because tumor cells are often killed by TRAIL and normal cells are not, drugs that activate the TRAIL pathway have been thought to have potential clinical value. However, to date, most TRAIL-related clinical trials have largely failed due to the tumor cells having intrinsic or acquired resistance to TRAIL-induced apoptosis. Previous studies to identify resistance mechanisms have focused on targeted analysis of the canonical apoptosis pathway and other known regulators of TRAIL receptor signaling. To identify novel mechanisms of TRAIL resistance in an unbiased way, we performed a genome-wide shRNA screen for genes that regulate TRAIL sensitivity in sublines that had been selected for acquired TRAIL resistance. This screen identified previously unknown mediators of TRAIL resistance including angiotensin II receptor 2, Crk-like protein, T-Box Transcription Factor 2, and solute carrier family 26 member 2 (SLC26A2). SLC26A2 downregulates the TRAIL receptors, DR4 and DR5, and this downregulation is associated with resistance to TRAIL. Its expression is high in numerous tumor types compared with normal cells, and in breast cancer, SLC26A2 is associated with a significant decrease in relapse-free survival.

Original languageEnglish
Pages (from-to)382-394
Number of pages13
JournalMolecular Cancer Research
Volume15
Issue number4
DOIs
Publication statusPublished - 2017 Apr 1
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Dimberg, L. Y., Towers, C. G., Behbakht, K., Hotz, T. J., Kim, J., Fosmire, S., Porter, C. C., Tan, A-C., Thorburn, A., & Ford, H. L. (2017). A genome-wide loss-of-function screen identifies SLC26A2 as a novel mediator of TRAIL resistance. Molecular Cancer Research, 15(4), 382-394. https://doi.org/10.1158/1541-7786.MCR-16-0234