Mechanistic Link Between HIF2 Alpha and p53 Uncovers New Treatment Approach for Renal Carcinoma Cells

Strategic Insights -

Researchers at the University of Toronto have made a significant discovery in understanding the relationship between hypoxia-inducible factor 2 alpha (HIF2 alpha) and the tumor suppressor protein p53. Their study reveals that the accumulation of HIF2 alpha, a critical oncogenic event in clear cell renal cell carcinoma (CCRCC), leads to Hdm2-mediated suppression of p53. This suppression is associated with increased resistance to chemotherapy and death receptor-induced death. The researchers found that the abrogation of Hdm2-p53 interaction using a small-molecule Hdm2 inhibitor or downregulating HIF2 alpha via specific RNA or reconstituting wild-type VHL restores p53 function and reverses the resistance of CCRCC cells to Fas-mediated and chemotherapy-induced cell death.

Key Takeaways:

  • The researchers identified a mechanistic link between HIF2 alpha and p53, a relationship that was previously unknown.
  • The study found that CCRCC cells exhibit increased levels of activated nuclear phospho-Hdm2(Ser(166)) and low p53 expression, suggesting a suppression of p53 activity.
  • The repression of p53 is associated with increased resistance to chemotherapy and death receptor-induced death.
  • The abrogation of Hdm2-p53 interaction using a small-molecule Hdm2 inhibitor or downregulating HIF2 alpha via specific RNA or reconstituting wild-type VHL restores p53 function and reverses the resistance of CCRCC cells to Fas-mediated and chemotherapy-induced cell death.
  • The research provides a rationale for combining Hdm2 antagonists with chemotherapy for the treatment of CCRCC.
  • The study was conducted at the University of Toronto and published in Cancer Research.

Statistics:

  • Cancer Research study: Cancer Res; 69(23); 9056-9064.
  • Exposure to hypoxia: Prolonged exposure to hypoxia triggers the accumulation of HIF2 alpha.
  • HIF2 alpha accumulation: Leads to Hdm2-mediated suppression of p53 in CCRCC cells.
  • Hdm2-p53 interaction: Abrogation using a small-molecule Hdm2 inhibitor restores p53 function.
  • Chemoresistance: CCRCC cells exhibit increased resistance to chemotherapy and death receptor-induced death.

Sources:

  • "Suppression of Hypoxia-inducible Factor 2 alpha Restores p53 Activity via Hdm2 and Reverses Chemoresistance of Renal Carcinoma Cells" [Cancer Research 2009;69(23):9056-64].
  • University of Toronto, Medical Department.
  • Carcinoma.
  • American Association Cancer Research, 615 Chestnut St., 17TH Floor, Philadelphia, PA 19106-4404, USA.
  • Cancer Weekly editors, staff, and other reports.