SET protein accumulation prevents cell death in head and neck squamous cell carcinoma through regulation of redox state and autophagy

Autor(es)

Ouchida, Amanda Tomie ^{[1, 2]} ; Uyemura, Valeria Tudella ^[1] ; Queiroz, Andre Lima ^[2] ; Brauer, Veronica Soares ^{[3, 2]} ; Cavalcanti-Neto, Marinaldo Pacifico ^{[1, 2]} ; Sousa, Lucas Oliveira ^[3] ; Uyemura, Sergio Akira ^[3] ; Curti, Carlos ^{[1, 2]} ; Leopoldino, Andreia Machado ^[3]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Phys & Chem, Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Grad Program Biochem, Ribeirao Preto, SP - Brazil

^[3] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, Dept Clin Analyses Toxicol & Food Sci, Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH; v. 1866, n. 4, p. 623-637, APR 2019.
• Citações Web of Science: 1

Resumo

Molecular alterations in cell death pathways and imbalances in regulators of up- or downstream signaling pathways can lead to resistance to cell death, which is one of the hallmarks of cancer. These signaling modifications are strategies that tumor cells use to resist chemotherapy and that contribute to the high recurrence rate of head and neck squamous cell carcinoma (HNSCC). The SET oncoprotein is a PP2A inhibitor that accumulates in HNSCC and represents a promising therapeutic target. Here we report the role that SET protein plays in resistance to death of two HNSCC cell lines: Cal 27 and HN13. SET protein regulated intracellular redox balance by controlling cellular localization of APE 1 an endonuclease that is part of the SET complex and regulates antioxidant gene transcription. SET protein knockdown (siSET) associated with tert-butyl hydroperoxide-induced oxidative stress sensitized Cal 27 and HN13 cells to apoptosis via the extrinsic and intrinsic pathways, respectively. SET protein upregulated autophagy in HNSCC cells in a PP2A-dependent manner and apparently regulated ULK1 expression. The fact that siSET lowered Bcl-2 phosphorylation levels indicated that SET protein interfered with an alternative pathway that modulated autophagy in HNSCC cells. Overall, SET protein regulated intracellular redox state and sustained autophagy in HNSCC cells, which may explain resistance to death of HNSCC cells. Altogether, the findings reported herein support SET protein as therapeutic target for HNSCC. (AU)

• Processo FAPESP: 16/19103-2 - SET e esfingolipídeos em câncer de cabeça e pescoço: sinalização, alvos e terapia antitumoral
• Beneficiário: Andréia Machado Leopoldino
• Linha de fomento: Auxílio à Pesquisa - Temático
• Processo FAPESP: 09/52228-0 - Estudos da resistência à apoptose no câncer, modelo cabeça/pescoço: vias de sinalização com ênfase na PIP3-AKT/SET, estresse oxidativo, mitocôndria e correlações
• Beneficiário: Carlos Curti
• Linha de fomento: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/10898-4 - Estudo dos mecanismos moleculares associados à proteína SET com impacto na tumorigênese e progressão do câncer oral
• Beneficiário: Carlos Curti
• Linha de fomento: Auxílio à Pesquisa - Regular