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WP1130 Enhances TRAIL-Induced Apoptosis through USP9X-Dependent miR-708-Mediated Downregulation of c-FLIP

Seok Kim1, Seon Min Woo2, Kyoung-Jin Min3

  • 1Department of Immunology, School of Medicine, Keimyung University, 1095 Dalgubeoldaero, Dalseo-Gu, Daegu 42601, Korea. kimseok216@naver.com.

Cancers
|March 14, 2019
PubMed

Insights

WP1130, a deubiquitinase inhibitor, enhances cancer cell apoptosis when combined with TRAIL therapy. This effect is mediated by USP9X inhibition, leading to reduced c-FLIP and increased sensitivity to TRAIL.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Deubiquitinase (DUB) inhibitors represent a promising therapeutic strategy in oncology.
  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis, but its clinical efficacy is often limited by resistance mechanisms.
  • c-FLIP (FLICE-inhibitory protein) is a key regulator of apoptosis that can confer resistance to TRAIL-induced cell death.

Purpose of the Study:

  • To investigate the sensitizing effect of WP1130, a DUB inhibitor, on TRAIL-induced apoptosis in human cancer cells.
  • To elucidate the molecular mechanisms underlying the combined effect of WP1130 and TRAIL.

Main Methods:

  • Treatment of human renal, lung, and hepatocellular carcinoma cell lines with WP1130 and TRAIL, alone and in combination.
  • Assessment of apoptosis induction using cell viability assays.
  • Analysis of c-FLIP protein expression levels.
  • Investigation of the role of microRNA-708 (miR-708) and USP9X in the observed effects through gene knockdown and ectopic expression studies.

Main Results:

  • Combination therapy with WP1130 and TRAIL significantly induced apoptosis in various cancer cell lines, including renal, lung, and hepatocellular carcinoma, while sparing normal cells.
  • The combined treatment led to the downregulation of c-FLIP protein expression.
  • WP1130-induced c-FLIP downregulation was mediated by the upregulation of miR-708, which was achieved through the inhibition of USP9X.
  • Knockdown of USP9X mimicked the effects of WP1130, causing c-FLIP downregulation, miR-708 upregulation, and enhanced sensitivity to TRAIL. Ectopic expression of USP9X abrogated these effects.

Conclusions:

  • WP1130 sensitizes cancer cells to TRAIL-induced apoptosis.
  • The mechanism involves the inhibition of USP9X, leading to miR-708 upregulation and subsequent downregulation of c-FLIP.
  • This study identifies a novel therapeutic strategy combining DUB inhibitors with TRAIL for cancer treatment.
Keywords:
DR5MicroRNATRAILWP1130c-FLIP

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