GRP75 and diet impact on Skin Cutaneous Melanoma development

Skin cutaneous melanoma (SKCM) is the deadliest form of skin cancer due to its high heterogeneity that drives tumor aggressiveness. Glucose Regulated Protein 75 (GRP75) is a member of the Heat Shock Protein 70 (HSP70) family, and it has several subcellular localizations and binding partners. It has been demonstrated that this protein is enriched in cancer cells, contributing to cellular proliferation, migration, and invasion through Protein Kinase B (AKT) activation and p53 sequestration. GRP75 also serves as a bridging factor between the Endoplasmic Reticulum (ER) and mitochondria; this coupling promotes Ca2+ mobilization, facilitating cell proliferation and modulating several pathways and metabolic processes. In this context, we generated a GRP75 knockdown model in the B16F10 murine cell line, demonstrating its key role in SKCM development and progression. Our findings highlight that GRP75 knockdown leads to impairment of melanoma cell proliferation and migration. Moreover, its modulation impacts on mitochondrial metabolism and ER-mitochondria contact site dynamic. Finally, we showed a clear correlation among different nutrient administration, GRP75 modulation and cancer cell proliferation. These findings reveal that affecting mitochondria-ER tethering may be beneficial against cancer altering cellular signaling, and in turn making tumor cells more susceptible to chemotherapy.