Mammalian target of rapamycin complex 2 (mTORC2) with its pivotal component rapamycin-insensitive companion of mTOR (RICTOR) is the major regulator of AKT phosphorylation and is increasingly implicated in tumor growth and progression.,In cutaneous melanoma, an extremely aggressive and highly metastatic disease, RICTOR overexpression is involved in tumor development and invasiveness.,Therefore, we investigated the impact of RICTOR inhibition in melanoma cells in vitro and in vivo with special emphasis on hepatic metastasis.,Moreover, our study focused on the interaction of tumor cells and hepatic stellate cells (HSC) which play a crucial role in the hepatic microenvironment.,In silico analysis revealed increased RICTOR expression in melanoma cells and tissues and indicated higher expression in advanced melanoma stages and metastases.,In vitro, transient RICTOR knock-down via siRNA caused a significant reduction of tumor cell motility.,Using a syngeneic murine splenic injection model, a significant decrease in liver metastasis burden was detected in vivo.,Moreover, stimulation of melanoma cells with conditioned medium (CM) from activated HSC or hepatocyte growth factor (HGF) led to a significant induction of AKT phosphorylation and tumor cell motility.,Blocking of RICTOR expression in cancer cells diminished constitutive and HGF-induced AKT phosphorylation as well as cell motility.,Interestingly, RICTOR blockade also led to an abrogation of CM-induced effects on AKT phosphorylation and motility in melanoma cells.,In conclusion, these results provide first evidence for a critical role of mTORC2/RICTOR in melanoma liver metastasis via cancer cell/HSC interactions.
UV radiation (UV) is classified as a “complete carcinogen” because it is both a mutagen and a non-specific damaging agent and has properties of both a tumor initiator and a tumor promoter.,In environmental abundance, UV is the most important modifiable risk factor for skin cancer and many other environmentally-influenced skin disorders.,However, UV also benefits human health by mediating natural synthesis of vitamin D and endorphins in the skin, therefore UV has complex and mixed effects on human health.,Nonetheless, excessive exposure to UV carries profound health risks, including atrophy, pigmentary changes, wrinkling and malignancy.,UV is epidemiologically and molecularly linked to the three most common types of skin cancer, basal cell carcinoma, squamous cell carcinoma and malignant melanoma, which together affect more than a million Americans annually.,Genetic factors also influence risk of UV-mediated skin disease.,Polymorphisms of the melanocortin 1 receptor (MC1R) gene, in particular, correlate with fairness of skin, UV sensitivity, and enhanced cancer risk.,We are interested in developing UV-protective approaches based on a detailed understanding of molecular events that occur after UV exposure, focusing particularly on epidermal melanization and the role of the MC1R in genome maintenance.