Melanoma is a malignant tumor with high mortality and continuously increasing prevalence. Recent studies in mice transgenic for hepatocyte growth factor / scatter factor (HGF/SF) elegantly demonstrated a causative role for a single high dose of ultraviolet (UV)-B (280-320nm) radiation in the development of melanoma. In contrast, evidence for a role of UV-A in processes participating in the pathogenesis of melanoma in humans remains elusive. Here, we provide in-vitro and in-vivo evidence in support of the notion that chronic exposure to low doses of UV-A plays a role in melanomagenesis. Chronic UV-A exposure transiently induces sensescence associated ß-galactosidase in normal melanocytes which is dramatically reduced in melanoma cell lines. Mutations of mitochondrial (mt)DNA, known to be induced by UV-A, mediated by ROS and reported to be present in other tumor entities, show an increase during the switch from dysplastic nevi to malignant melanoma. Markers for melanoma progression such as Akt and L1 are increased by UV-A, while apoptosis is unaffected or even reduced. Warburg-associated lactate and transketolase (TKTL)-1 are induced and mitochondrial function is disturbed. These effects can be inhibited by ROS-quenchers, inhibitors of TKTL-1 and inhibitors of glycolysis. Thus, these results indicate a role for chronic UV-A exposure in the pathogenesis of melanoma through alteration of processes involved in melanomagenesis such as senescence, increased levels of activated Akt and L1 protein, increased levels of ROS-associated mtDNA mutations and the Warburg effect.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3983.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO