Inhibition of cholesterol metabolism underlies synergy between mTOR pathway inhibition and chloroquine in bladder cancer cells

M. A. King (Lead / Corresponding author), I. G. Ganley, V. Flemington (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)
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Abstract

Mutations to fibroblast growth factor receptor 3 (FGFR3) and phosphatase and tensin homologue (PTEN) signalling pathway components (for example, PTEN loss, PIK3CA, AKT1, TSC1/2) are common in bladder cancer, yet small-molecule inhibitors of these nodes (FGFR/PTENi) show only modest activity in preclinical models. As activation of autophagy is proposed to promote survival under FGFR/PTENi, we have investigated this relationship in a panel of 18 genetically diverse bladder cell lines. We found that autophagy inhibition does not sensitise bladder cell lines to FGFR/PTENi, but newly identify an autophagy-independent cell death synergy in FGFR3-mutant cell lines between mTOR (mammalian target of rapamycin) pathway inhibitors and chloroquine (CQ)-an anti-malarial drug used as a cancer therapy adjuvant in over 30 clinical trials. The mechanism of synergy is consistent with lysosomal cell death (LCD), including cathepsin-driven caspase activation, and correlates with suppression of cSREBP1 and cholesterol biosynthesis in sensitive cell lines. Remarkably, loss of viability can be rescued by saturating cellular membranes with cholesterol or recapitulated by statin-mediated inhibition, or small interfering RNA knockdown, of enzymes regulating cholesterol metabolism. Modulation of CQ-induced cell death by atorvastatin and cholesterol is reproduced across numerous cell lines, confirming a novel and fundamental role for cholesterol biosynthesis in regulating LCD. Thus, we have catalogued the molecular events underlying cell death induced by CQ in combination with an anticancer therapeutic. Moreover, by revealing a hitherto unknown aspect of lysosomal biology under stress, we propose that suppression of cholesterol metabolism in cancer cells should elicit synergy with CQ and define a novel approach to future cancer treatments.

Original languageEnglish
Pages (from-to)4518-4528
Number of pages11
JournalOncogene
Volume35
Issue number34
Early online date8 Feb 2016
DOIs
Publication statusPublished - 25 Aug 2016

Keywords

  • Atorvastatin calcium
  • Autophagy
  • Cell line, Tumor
  • Cell membrane permeability
  • Chloroquine
  • Cholesterol
  • Drug synergism
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Lysosomes
  • PTEN Phosphohydrolase
  • Proto-Oncogene Proteins c-akt
  • Receptors, Fibroblast growth factor
  • Signal transduction
  • TOR Serine-Threonine kinases
  • Urinary bladder neoplasms

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