title: Inhibition of the RhoA GTPase Activity Increases Sensitivity of Melanoma Cells to UV Radiation Effects.
abstract: Ultraviolet radiation is the main cause of DNA damage to melanocytes and development of melanoma, one of the most lethal human cancers, which leads to metastasis due to uncontrolled cell proliferation and migration. These phenotypes are mediated by RhoA, a GTPase overexpressed or overactivated in highly aggressive metastatic tumors that plays regulatory roles in cell cycle progression and cytoskeleton remodeling. This work explores whether the effects of UV on DNA damage, motility, proliferation, and survival of human metastatic melanoma cells are mediated by the RhoA pathway. Mutant cells expressing dominant-negative (MeWo-RhoA-N19) or constitutively active RhoA (MeWo-RhoA-V14) were generated and subjected to UV radiation. A slight reduction in migration and invasion was observed in MeWo and MeWo-RhoA-V14 cells but not in MeWo-RhoA-N19 cells, which presented inefficient motility and invasiveness associated with stress fibers fragmentation. Proliferation and survival of RhoA-deficient cells were drastically reduced by UV compared to cells displaying normal or high RhoA activity, suggesting increased sensitivity to UV. Loss of RhoA activity also caused less efficient DNA repair, with elevated levels of DNA lesions such as strand breaks and cyclobutane pyrimidine dimers (CPDs). Thus, RhoA mediates genomic stability and represents a potential target for sensitizing metastatic tumors to genotoxic agents.
authors.affiliation: Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, 05508-000 Sao Paulo, SP, Brazil.
authors.forename: Gisele
authors.initials: G
authors.lastname: Espinha
authors.affiliation: Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, 05508-000 Sao Paulo, SP, Brazil.
authors.forename: Juliana Harumi
authors.initials: JH
authors.lastname: Osaki
authors.affiliation: Centro de Oncologia Molecular, Hospital Sirio Libanes, 01308-060 Sao Paulo, SP, Brazil; Ludwig Institute for Cancer Research (LICR), 01509-010 Sao Paulo, SP, Brazil.
authors.forename: Erico Tosoni
authors.initials: ET
authors.lastname: Costa
authors.affiliation: Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, 05508-000 Sao Paulo, SP, Brazil.
authors.forename: Fabio Luis
authors.initials: FL
authors.lastname: Forti
mesh_terms: D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor / Q000528:radiation effects; D002465:Cell Movement; D049109:Cell Proliferation; D020552:Comet Assay; D004249:DNA Damage; D004260:DNA Repair; D019204:GTP-Binding Proteins; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008856:Microscopy, Fluorescence; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011740:Pyrimidine Dimers / Q000737:chemistry; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology; D014466:Ultraviolet Rays; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011740:Pyrimidine Dimers; C100494:RTKN protein, human; C066737:RHOA protein, human; D005982:Glutathione Transferase; D019204:GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
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