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Metabolic stressors disrupt proteome homeostasis to suppress malignancy

Chengkai Dai1

  • 1The Jackson Laboratory, Bar Harbor, ME 04609, USA.

Molecular & Cellular Oncology
|March 15, 2016
PubMed

Insights

Metabolic stressors like metformin inactivate heat shock factor 1 (HSF1) in tumor cells. This disrupts proteome homeostasis, hindering cancer growth and offering a novel therapeutic strategy.

Area of Science:

  • Cellular stress response
  • Cancer biology
  • Proteostasis mechanisms

Background:

  • Tumor cells rely on the heat shock factor 1 (HSF1) stress response to maintain proteome homeostasis.
  • Constitutive HSF1 activation supports malignant phenotypes and tumor survival.
  • Persistent proteotoxic stress is a hallmark of cancer cells.

Purpose of the Study:

  • To investigate the impact of metabolic stressors on HSF1 activity in cancer.
  • To explore the potential of targeting HSF1 via metabolic interventions for cancer therapy.
  • To elucidate the mechanisms by which metabolic stress affects proteomic stability in tumors.

Main Methods:

  • Utilized cell culture models of cancer.
  • Administered metabolic stressors, including metformin.
  • Assessed HSF1 activity and downstream stress response markers.
  • Analyzed proteomic profiles to evaluate cellular chaos.

Main Results:

  • Metabolic stressors, exemplified by metformin, were found to inactivate HSF1.
  • Inactivation of HSF1 led to significant proteomic chaos within tumor cells.
  • Disruption of proteostasis by metformin impeded tumorigenesis.
  • HSF1 inactivation represents a critical vulnerability in cancer cells.

Conclusions:

  • Targeting HSF1 through metabolic interventions offers a promising strategy to combat cancer.
  • Metformin and similar agents can disrupt cancer cell survival by destabilizing proteome homeostasis.
  • Understanding the HSF1-mediated stress response is crucial for developing new anti-cancer therapies.
Keywords:
AMPKHSF1glucose deprivationmetabolic stressmetforminproteostasisproteotoxic stresstumor suppressionubiquitination

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