Desensitization of basal cell carcinoma to the anti-tumoral effect of vitamin D: Role of REDD1

Document Type

Conference Proceeding

Publication Date


Publication Title

FASEB Journal


The relationship between vitamin D and non-melanoma skin cancer is not clear. Epidemiological studies are inconsistent and inconclusive, and mechanistic studies are lacking. Vitamin D is a seco-steroid hormone, whose nuclear receptor, vitamin D receptor (VDR), is a nuclear transcription factor. It has been suggested that vitamin D possesses anti-proliferative and pro-differentiation effects by negatively regulating important signaling pathways. In particular, the VDR target gene - regulated in development and DNA damage response 1 (REDD1) - inhibits the mechanistic target of rapamycin (mTOR) pathway, thus impacting cellular growth. In response to DNA damage, REDD1 transcription is up-regulated by elevated levels of tumor protein 53(p53), resulting in inhibition of mTOR pathway. Subsequently, reduction ofp53 results in feedback inhibition at the translation level. This case-control study aimed to explore the impact of vitamin D status on the onset and progression and possibly treatment of basal cell carcinoma (BCC). Three tissue samples were collected from 20 BCC patients (Cancer, Proximal, and Distal), and 6 cancer-free individuals from southeast Michigan. BCC and its feeding cells seemed to up-regulate vitamin D activation enzymes, VDR, and its co-activators, thus proposing higher local activity of vitamin D. Despite the significantly increased protein levels of REDD1 in the cancer tissue, our data showed that VRD's ability to down-regulate mTOR pathway through REDD1 was diminished. Interestingly, Vitamin D negative regulation of Hedgehog-Gli pathways was also lost in the cancer tissue. A gain of function mutation in the Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), upstream of mTOR pathway, was detected in all BCC specimens. In conclusion, we propose that the anticipated role of vitamin D is not conserved in BCC tissue, possibly related to additional mutations.




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