Graduate Program in Biochemistry, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil; Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
Biochim Biophys Acta Mol Cell Res. 2019 Apr;1866(4):623-637. doi: 10.1016/j.bbamcr.2019.01.005. Epub 2019 Jan 16.
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.
细胞死亡途径中的分子改变以及上下游信号通路调节因子的失衡可导致细胞死亡抵抗，这是癌症的特征之一。这些信号转导修饰是肿瘤细胞用于抵抗化疗的策略，也是导致头颈部鳞状细胞癌（HNSCC）高复发率的原因之一。SET 癌蛋白是一种 PP2A 抑制剂，在 HNSCC 中积累，是有前途的治疗靶点。本研究报道了 SET 蛋白在两种 HNSCC 细胞系（Cal 27 和 HN13）抵抗死亡中的作用。SET 蛋白通过控制 APE1 的细胞定位来调节细胞内氧化还原平衡，APE1 是 SET 复合物的一部分，可调节抗氧化基因转录。SET 蛋白敲低（siSET）与叔丁基过氧化物诱导的氧化应激一起，分别通过外在和内在途径使 Cal 27 和 HN13 细胞对细胞凋亡敏感。SET 蛋白以 PP2A 依赖的方式在上皮性肿瘤细胞中上调自噬，并且显然调节 ULK1 的表达。siSET 降低 Bcl-2 磷酸化水平的事实表明，SET 蛋白干扰了调节上皮性肿瘤细胞自噬的替代途径。总之，SET 蛋白调节了 HNSCC 细胞的细胞内氧化还原状态并维持了自噬，这可能解释了 HNSCC 细胞抵抗死亡的原因。总的来说，本研究结果支持 SET 蛋白作为 HNSCC 的治疗靶点。
