NADPH accumulation is responsible for apoptosis in breast cancer cells induced by fatty acid synthase inhibition.
NADPH accumulation is responsible for apoptosis in breast cancer cells induced by fatty acid synthase inhibition.
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NADPH 积累是脂肪酸合酶抑制诱导乳腺癌细胞凋亡的原因
DOI：
10.18632/oncotarget.15936
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发表时间：
2017-05-16
期刊：
影响因子：
--
通讯作者：
Li B
中科院分区：
文献类型：
--
作者：
Cui Y;Xing P;Wang Y;Liu M;Qiu L;Ying G;Li B
脂肪酸合成酶(Fas)作为一种参与新生脂肪生成的关键酶，在多种肿瘤中都有高表达。Fas抑制在体内和体外诱导细胞死亡，使Fas成为肿瘤治疗的一个有吸引力的靶点，但其确切的机制仍不清楚。在此，我们证实Fas在乳腺癌中高表达，并通过其抑制剂或基因敲除抑制Fas诱导乳腺癌细胞的凋亡。我们的结果表明，Fas抑制可诱导乳腺癌细胞产生高水平的活性氧，但与细胞的凋亡无关。相反，通过抑制Fas导致的NADPH积聚被发现刺激NADPH氧化酶产生活性氧物种，并与诱导细胞凋亡高度相关。抑制NADPH氧化酶几乎完全阻止了活性氧的产生，同时通过抑制Fas显著增强了体外和体内对乳腺癌的杀伤作用。综上所述，这些数据表明，Fas在维持细胞氧化还原动态平衡中起关键作用，其抑制导致NADPH积聚介导的细胞凋亡。我们的发现可能为癌症新陈代谢提供新的见解，并有助于设计有效的抗癌治疗方法。
Fatty acid synthase (FAS), as a key enzyme involved in de novo lipogenesis, is highly expressed in many cancers. FAS inhibition induces cell death in vivo and in vitro, rendering FAS as an attractive target for cancer therapy, but the defined mechanism is still not well understood. Herein, we confirmed that FAS was highly expressed in breast cancers and FAS inhibition by its inhibitors or knockdown induced apoptosis in breast cancer cells. Our results showed that a significantly high level of reactive oxygen species was induced but not responsible for apoptosis in breast cancer cells by FAS inhibition. Instead, NADPH accumulation resulting from FAS inhibition was found to stimulate NADPH oxidase to generate reactive oxygen species and highly associated with apoptosis induction. Suppression of NADPH oxidase almost totally blocked reactive oxygen species generation while significantly potentiated the in vitro and in vivo killing of breast cancers by FAS inhibition. Taken together, these data suggest that FAS plays a critical role in maintaining cellular redox homeostasis and its inhibition leads to NADPH accumulation-mediated apoptosis. Our finding may provide new insights into cancer metabolism and aid in designing effective anticancer treatments.