AI Article Synopsis

  • HIFs promote cancer growth and angiogenesis, with their activity regulated by hydroxylases that require ascorbate as a cofactor.
  • Clear cell renal cell carcinomas (ccRCC) have mutations in the VHL gene, leading to different responses to ascorbate compared to papillary RCC (pRCC) which has a functional VHL.
  • Ascorbate levels impact HIF activity in VHL-proficient tumors (like pRCC), but do not affect HIF response in VHL-defective ccRCC, highlighting its role in modulating tumor aggression in certain cancers.

Article Abstract

Hypoxia-inducible transcription factors (HIFs) drive angiogenesis and cancer cell growth, contributing to an aggressive tumor phenotype. HIF-α protein levels and activity are controlled at the post-translational level by HIF hydroxylases. Hydroxylated HIF-α is recognized by the von Hippel Lindau (VHL) tumor suppressor and targeted for degradation. The HIF hydroxylases are members of the iron and 2-oxoglutarate-dependent dioxygenases, which require ascorbate as cofactor for activity. Clear cell renal cell carcinomas (ccRCC) harbor mutations in the gene, whereas papillary RCC (pRCC) have a functional VHL. These natural occurring variants in RCC enable the testing, in clinical samples, of the hypothesis that ascorbate modulates HIF-α levels through its role as a cofactor for the HIF hydroxylases. We measured ascorbate, HIF-1α, and HIF-2α protein and HIF downstream targets BNIP3, CA9, cyclin D1, GLUT1, and VEGF (combined to generate the HIF pathway score) in VHL-defective ccRCC ( = 73) and VHL-proficient pRCC human tumor tissue ( = 41). HIF and ascorbate levels were increased in ccRCC and pRCC tumors compared to matched renal cortex. HIF-1 and total HIF pathway activation scores were decreased with higher ascorbate in pRCC tumors (Spearman = -0.38, < 0.05 and = -0.35, < 0.05). This was not evident for ccRCC tumors. In mechanistic studies , ascorbate influenced HIF-1 activity in VHL-proficient, but not VHL-defective ccRCC cells. Our results indicate that ccRCC, which lacks a functional VHL, does not respond to ascorbate-mediated modulation of the HIF response. This contrasts with the demonstrated association between ascorbate content and the HIF pathway observed in pRCC and other tumors with a functional VHL. The results support a role for ascorbate as a modulator of HIF activity and tumor aggression in cancer types with a functional hypoxic response.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284050PMC
http://dx.doi.org/10.3389/fonc.2018.00574DOI Listing

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