Proanthocyanidins inhibit photocarcinogenesis through enhancement of DNA repair and xeroderma pigmentosum group A-dependent mechanism.
Dietary grape seed proanthocyanidins (GSP) inhibit photocarcinogenesis in mice; however, the molecular mechanisms underlying this effect have not been fully elucidated. As ultraviolet B (UVB)-induced DNA damage in the form of cyclobutane pyrimidine dimers (CPDs) has been implicated in skin cancer risk, we studied whether dietary GSPs enhance repair of UVB-induced DNA damage and, if so, what is the potential mechanism? Supplementation of GSPs (0.5%, w/w) with AIN76A control diet significantly reduced the levels of CPD(+) cells in UVB-exposed mouse skin; however, GSPs did not significantly reduce UVB-induced CPD(+) cells in the skin of interleukin-12p40 (IL-12) knockout (KO) mice, suggesting that IL-12 is required for the repair of CPDs by GSPs. Using IL-12 KO mice and their wild-type counterparts and standard photocarcinogenesis protocol, we found that supplementation of control diet with GSPs (0.5%, w/w) significantly reduced UVB-induced skin tumor development in wild-type mice, which was associated with the elevated mRNA levels of nucleotide excision repair genes, such as XPA, XPC, DDB2, and RPA1; however, this effect of GSPs was less pronounced in IL-12 KO mice. Cytostaining analysis revealed that GSPs repaired UV-induced CPD(+) cells in xeroderma pigmentosum complementation group A (XPA)-proficient fibroblasts from a healthy individual but did not repair in XPA-deficient fibroblasts from XPA patients. Furthermore, GSPs enhance nuclear translocation of XPA and enhanced its interactions with other DNA repair protein ERCC1. Together, our findings reveal that prevention of photocarcinogenesis by GSPs is mediated through enhanced DNA repair in epidermal cells by IL-12- and XPA-dependent mechanisms.
Vaid
Mudit
M
Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Sharma
Som D
SD
Katiyar
Santosh K
SK
D000818:Animals; D015153:Blotting, Western; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics; D004032:Diet; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D056604:Grape Seed Extract / Q000627:therapeutic use*; D006801:Humans; D007124:Immunoenzyme Techniques; D018664:Interleukin-12 / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000517:prevention & control*; D044945:Proanthocyanidins / Q000627:therapeutic use*; D011740:Pyrimidine Dimers / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014466:Ultraviolet Rays; D027843:Vitis / Q000737:chemistry; D051760:Xeroderma Pigmentosum Group A Protein / Q000502:physiology*
C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D056604:Grape Seed Extract; C511402:Grape Seed Proanthocyanidins; D044945:Proanthocyanidins; D011740:Pyrimidine Dimers; D012333:RNA, Messenger; D051760:Xeroderma Pigmentosum Group A Protein; D018664:Interleukin-12