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Inhibition of multiple CDKs potentiates colon cancer chemotherapy via p73-mediated DR5 induction

Jingshan Tong1,2, Xiao Tan1,2, Suisui Hao1,2

  • 1UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA.

Oncogene
|January 31, 2023
PubMed

Insights

Cyclin-dependent kinase inhibitors (CDKIs) induce cancer cell death by activating Death Receptor 5 (DR5) through the p73 protein. This pathway enhances chemotherapy effectiveness in colorectal cancer (CRC) treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Targeting cyclin-dependent kinases (CDKs) is a key strategy in cancer therapy.
  • The precise anticancer mechanisms of various CDK inhibitors (CDKIs) remain incompletely understood.
  • Previous research identified a role for selective CDK4/6 inhibitors in sensitizing colorectal cancer (CRC) cells to apoptosis via Death Receptor 5 (DR5) induction through p73.

Purpose of the Study:

  • To investigate whether the p73-mediated DR5 induction pathway is involved in the anticancer effects of diverse CDKIs.
  • To elucidate the molecular mechanisms underlying DR5 induction by less-selective CDKIs.
  • To assess the synergistic potential of CDKIs with 5-fluorouracil (5-FU) in colorectal cancer treatment.

Main Methods:

  • Treatment of colorectal cancer cells with various CDKIs (flavopiridol, roscovitine, dinaciclib, SNS-032).
  • Analysis of Death Receptor 5 (DR5) and p73 expression and localization.
  • Assessment of p73 phosphorylation at Threonine 86.
  • Knockdown of CDK1, CDK2, or CDK9.
  • In vitro and in vivo studies evaluating the synergy between CDKIs and 5-fluorouracil (5-FU).

Main Results:

  • Less-selective CDKIs induced DR5 expression through p73-mediated transcriptional activation.
  • DR5 induction by CDKIs was linked to p73 dephosphorylation at Threonine 86 and subsequent nuclear translocation.
  • Knockdown of CDK1, CDK2, or CDK9 mimicked the p73-mediated DR5 induction.
  • CDKIs demonstrated significant synergy with 5-FU, enhancing growth suppression and apoptosis in CRC cells, dependent on DR5 and p73.

Conclusions:

  • p73-mediated DR5 induction represents a tumor suppressive mechanism engaged by various CDKIs.
  • This pathway is critical for CDKIs to potentiate therapy-induced apoptosis in colorectal cancer cells.
  • Understanding this mechanism can guide the clinical development and application of CDKIs in CRC treatment.

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