Downregulation of PHLPP expression contributes to hypoxia-induced resistance to chemotherapy in colon cancer cells

Yang An Wen, Payton D. Stevens, Michael L. Gasser, Romina Andrei, Tianyan Gao

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Hypoxia is a feature of solid tumors. Most tumors are at least partially hypoxic. This hypoxic environment plays a critical role in promoting resistance to anticancer drugs. PHLPP, a novel family of Ser/Thr protein phosphatases, functions as a tumor suppressor in colon cancers. Here, we show that the expression of both PHLPP isoforms is negatively regulated by hypoxia/anoxia in colon cancer cells. Interestingly, a hypoxia-induced decrease of PHLPP expression is attenuated by knocking down HIF1α but not HIF2α. Whereas the mRNA levels of PHLPP are not significantly altered by oxygen deprivation, the reduction of PHLPP expression is caused by decreased protein translation downstream of mTOR and increased degradation. Specifically, hypoxiainduced downregulation of PHLPP is partially rescued in TSC2 or 4E-BP1 knockdown cells as the result of elevated mTOR activity and protein synthesis. Moreover, oxygen deprivation destabilizes PHLPP protein by decreasing the expression of USP46, a deubiquitinase of PHLPP. Functionally, downregulation of PHLPP contributes to hypoxia-induced chemoresistance in colon cancer cells. Taken together, we have identified hypoxia as a novel mechanism by which PHLPP is downregulated in colon cancer, and the expression of PHLPP may serve as a biomarker for better understanding of chemoresistance in cancer treatment.

Original languageEnglish
Pages (from-to)4594-4605
Number of pages12
JournalMolecular and Cellular Biology
Volume33
Issue number22
DOIs
StatePublished - Nov 15 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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