Metformin-induced chemosensitization to cisplatin depends on P53 status and is inhibited by Jarid1b overexpression in non-small cell lung cancer cells

Autor(es)

Tortelli, Jr., Tharcisio Citrangulo ^{[1, 2]} ; Tamura, Rodrigo Esaki ^{[1, 2, 3]} ; Junqueira, Mara de Souza ^{[1, 2]} ; Mororo, Janio da Silva ^{[1, 2]} ; Bustos, Silvina Odete ^{[1, 2]} ; Natalino, Renato Jose Mendonca ^{[1, 2]} ; Russell, Shonagh ^[4] ; Desaubry, Laurent ^[5] ; Strauss, Bryan Eric ^{[1, 2]} ; Chammas, Roger ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ctr Invest Translac Oncol LIM24, Dept Radiol & Oncol, Fac Med, BR-01246000 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Inst Canc Estado Sao Paulo, BR-01246000 Sao Paulo, SP - Brazil

^[3] Univ Fed Sao Paulo, Lab Canc Mol Biol, BR-04039002 Sao Paulo, SP - Brazil

^[4] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Physiol, Tampa, FL 33612 - USA

^[5] Univ Strasbourg, CRBS, Lab Regenerat Nanomed RNM, INSERM, U1260, F-67000 Strasbourg - France

• Tipo de documento: Artigo Científico
• Fonte: AGING-US; v. 13, n. 18, p. 21914-21940, SEP 30 2021.
• Citações Web of Science: 0

Resumo

Metformin has been tested as an anti-cancer therapy with potential to improve conventional chemotherapy. However, in some cases, metformin fails to sensitize tumors to chemotherapy. Here we test if the presence of P53 could predict the activity of metformin as an adjuvant for cisplatin-based therapy in non-small cell lung cancer (NSCLC). A549, HCC 827 (TP53 WT), H1299, and H358 (TP53 null) cell lines were used in this study. A549 cells were pre-treated with a sub-lethal dose of cisplatin to induce chemoresistance. The effects of metformin were tested both in vitro and in vivo and related to the ability of cells to accumulate Jarid1b, a histone demethylase involved in cisplatin resistance in different cancers. Metformin sensitized A549 and HCC 827 cells (but not H1299 and H358 cells) to cisplatin in a P53-dependent manner, changing its subcellular localization to the mitochondria. Treatment with a sub-lethal dose of cisplatin increased Jarid1b expression, yet downregulated P53 levels, protecting A549Res cells from metformin-induced chemosensitization to cisplatin and favored a glycolytic phenotype. Treatment with FL3, a synthetic flavagline, sensitized A549Res cells to cisplatin. In conclusion, metformin could potentially be used as an adjuvant for cisplatin-based therapy in NSCLC cells if wild type P53 is present. (AU)

• Processo FAPESP: 15/26580-9 - Terapia gênica do câncer: alinhamento estratégico para estudos translacionais
• Beneficiário: Bryan Eric Strauss
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 19/08147-7 - Análise do perfil metabólico e modelagem matemática de células A549 de NSCLC, quimiorresistentes através da superexpressão de Jardi1b induzida por cisplatina
• Beneficiário: Tharcisio Citrangulo Tortelli Junior
• Modalidade de apoio: Bolsas no Exterior - Pesquisa
• Processo FAPESP: 15/22814-5 - Câncer e coração: novos paradigmas de diagnóstico e tratamento
• Beneficiário: Carlos Eduardo Negrão
• Modalidade de apoio: Auxílio à Pesquisa - Temático