Taken together, <i>t</i>RA combined with an ATM inhibitor can greatly enhance the anti-angiogenic activity of SerRS under UV irradiation and could be a better strategy in protecting skin from angiogenesis-associated skin damage and melanoma caused by UV radiation.
Loss-of-function melanocortin 1 receptor (MC1R) polymorphisms are common in UV-sensitive fair-skinned individuals and are associated with blunted cAMP second messenger signalling and higher lifetime risk of melanoma because of diminished ability of melanocytes to cope with UV damage. cAMP signalling positions melanocytes to resist UV injury by upregulating synthesis of UV-blocking eumelanin pigment and by enhancing the repair of UV-induced DNA damage. cAMP enhances melanocyte nucleotide excision repair (NER), the genome maintenance pathway responsible for the removal of mutagenic UV photolesions, through cAMP-activated protein kinase (protein kinase A)-mediated phosphorylation of the ataxia telangiectasia-mutated and Rad3-related (ATR) protein on the S435 residue.
Pretreatment of several melanoma lines just before gamma-irradiation with the inhibitor of ATM kinase KU-55933 suppressed p53 and nuclear factor-kappaB (NF-kappaB) activation but notably increased radiation-induced DR5 surface expression, down-regulated cFLIP (caspase-8 inhibitor) levels, and substantially enhanced exogenous TRAIL-induced apoptosis.
In line with efforts to identify genes that are key regulators of the disease and as such, may prove valuable targets for adjuvant and neo-adjuvant therapy of melanomas, we previously reported the presence of Serial Analysis of Gene Expression (SAGE) tags, corresponding to the Ataxia Telangiectasia Mutated (ATM) gene, in SAGE libraries generated from tissues representing primary and metastatic melanomas.
Multifactorially adjusted hazard ratios for ATMSer49Cys heterozygotes versus noncarriers were 1.2 (95% CI, 0.9 to 1.5) for cancer overall, 0.8 (95% CI, 0.3 to 2.0) for breast cancer, 4.8 (95% CI, 2.2 to 11) for melanoma, 2.3 (95% CI, 1.1 to 5.0) for prostate cancer, and 3.4 (95% CI, 1.1 to 11) for cancer of the oral cavity/pharynx.
Here, we demonstrate that tyrosinase which is commonly overexpressed in melanoma activates the bioflavonoid quercetin (Qct) and promotes an ataxia telangiectasia mutated (ATM)-dependent DNA damage response.
Ataxia telangiectasia-mutated gene is a possible biomarker for discrimination of infiltrative deep penetrating nevi and metastatic vertical growth phase melanoma.