| Autor: |
Carvalho LADC; Department of Tumor Biology, Moffitt Cancer Center, Tampa, FL 33612, USA.; Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, SP, Brazil., Noma IHY; Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, SP, Brazil., Uehara AH; Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, SP, Brazil., Siena ÁDD; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil., Osaki LH; Department of Cell Biology and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, SP, Brazil., Mori MP; Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo 05508-000, SP, Brazil., Pinto NCS; Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo 05508-000, SP, Brazil., Freitas VM; Department of Cell Biology and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, SP, Brazil., Junior WAS; Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil., Smalley KSM; Department of Tumor Biology, Moffitt Cancer Center, Tampa, FL 33612, USA., Maria-Engler SS; Department of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo 05508-000, SP, Brazil. |
| Abstrakt: |
Microenvironment and transcriptional plasticity generate subpopulations within the tumor, and the use of BRAF inhibitors (BRAFis) contributes to the rise and selection of resistant clones. We stochastically isolated subpopulations (C1, C2, and C3) from naïve melanoma and found that the clones demonstrated distinct morphology, phenotypic, and functional profiles: C1 was less proliferative, more migratory and invasive, less sensitive to BRAFis, less dependent on OXPHOS, more sensitive to oxidative stress, and less pigmented; C2 was more proliferative, less migratory and invasive, more sensitive to BRAFis, less sensitive to oxidative stress, and more pigmented; and C3 was less proliferative, more migratory and invasive, less sensitive to BRAFis, more dependent on OXPHOS, more sensitive to oxidative stress, and more pigmented. Hydrogen peroxide plays a central role in oxidative stress and cell signaling, and PRDXs are one of its main consumers. The intrinsically resistant C1 and C3 clones had lower MITF, PGC-1α, and PRDX1 expression, while C1 had higher AXL and decreased pigmentation markers, linking PRDX1 to clonal heterogeneity and resistance. PRDX2 is depleted in acquired BRAFi-resistant cells and acts as a redox sensor. Our results illustrate that decreased pigmentation markers are related to therapy resistance and decreased antioxidant defense. |
