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Vitamin D resistance in RAS-transformed keratinocytes: mechanism and reversal strategies

C Solomon1, R Kremer, J H White

  • 1Department of Medicine, Royal Victoria Hospital, McGill University, Montreal, Quebec, H3A 1A1, Canada.

Radiation Research
|December 20, 2000
PubMed

Insights

RAS-transformed cancer cells resist vitamin D signaling due to human retinoid X receptor alpha (hRXRalpha) phosphorylation. Inhibiting this phosphorylation or using specific vitamin D analogs restores sensitivity, offering new cancer treatment strategies.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Endocrinology

Background:

  • Human retinoid X receptor alpha (hRXRalpha) is crucial for DNA binding and transcriptional activity, often partnering with the vitamin D receptor (VDR).
  • Certain cancer cell lines exhibit resistance to the growth-inhibitory effects of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the active form of vitamin D.
  • Understanding the mechanisms of this resistance is vital for developing effective cancer therapies.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying resistance to vitamin D signaling in RAS-transformed keratinocytes.
  • To identify strategies for overcoming this resistance and restoring sensitivity to vitamin D and its analogs.

Main Methods:

  • Investigated the role of the RAS-RAF-MAP kinase cascade in hRXRalpha phosphorylation.
  • Utilized a MAP kinase inhibitor (PD098059) and a non-phosphorylatable hRXRalpha mutant (Ala260) to assess their impact on vitamin D signaling.
  • Compared the efficacy of 1,25(OH)(2)D(3) and a low-calcemic vitamin D analog (EB1089) in inhibiting cancer cell growth.

Main Results:

  • Phosphorylation of hRXRalpha at Ser260, mediated by the RAS-RAF-MAP kinase cascade, inhibits vitamin D signaling through VDR/hRXRalpha heterodimers.
  • The MAP kinase inhibitor PD098059 and the Ala260 hRXRalpha mutant reversed this inhibition, restoring sensitivity to 1,25(OH)(2)D(3) and the RXR ligand LG1069.
  • The vitamin D analog EB1089 demonstrated greater potency than 1,25(OH)(2)D(3) in inhibiting cancer cell proliferation.

Conclusions:

  • hRXRalpha phosphorylation is a key mechanism of resistance to vitamin D signaling in RAS-transformed cancer cells.
  • Targeted inhibition of hRXRalpha phosphorylation, combined with selective vitamin D analogs like EB1089, represents a promising therapeutic strategy for cancer treatment.

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