SYNUCLEINS AS ONCOGENIC PLAYERS: EXPLORING THE IMPACT OF NEURODEGENERATION-LINKED PROTEINS ALPHA AND GAMMA SYNUCLEIN IN MELANOMA

LUCIA ZANOTTI; FLORENCIA MALIZIA; MACARENA MAMBERTO; AVILA, AYLÉN; NAHUEL CESATTI LALUCE; LUCIANO ANSELMINO; MAURICIO MENACHO MÁRQUEZ

Congreso; REUNIÓN CONJUNTA SAIC SAFIS ALACF 2024; 2024

Synucleins are small, highly conserved proteins that playsignificant roles in both neurodegenerative disorders andcancer. These unstructured proteins are prone to aggregation, contributing to severe human diseases. Geneenrichment analyses associated with aS and gS revealthat all synuclein family members are involved in cell signaling pathways linked to disease, particularly in cancer.While the association of gS with cancer is well-established, recent studies have suggested a potential role foraS in this pathology. Our goal was to explore the role aSand gS in melanoma.Through an initial bioinformatic analysis, we confirmedthe expression of aS and gS in melanoma patients. Subsequently, we conducted experiments using human andmouse melanoma cell lines (SK-MEL28, A375, B16-F0,and B16-F10), where we verified the expression of theseproteins through the use of specific antibodies.To investigate the functional role of these proteins, wemodulated endogenous expression levels using shRNAand expression vectors. The downregulation of aS andgS resulted in a significant decrease in proliferation, clonogenic capacity and migration. These findings were futher validated in an in vivo model where mice inoculatedwith these modified cells exhibited reduced tumor growthand diminished metastasis. Moreover, cells overexpressing synucleins were found to be associated with cytoskeletal reorganization, increased migration and enhancedfocal adhesion formation. Nonetheless, they also exhibita higher apoptotic rate.In a complementary approach, we exogenously administered aS and gS. Rather than exerting cytotoxic effects,these exogenous proteins were observed to promoteproliferation, clonogenic potential, migration, and tumorgrowth.In conclusion, our study confirms the involvement of synucleins in melanoma, affecting key cancer-related processes. The observed effects of these proteins on tumorgrowth and cell behavior underscore their potential significance in cancer research. Further investigations areneeded to better understand their roles.