Targeting HIBCH to reprogram valine metabolism for the treatment of colorectal cancer
Targeting HIBCH to reprogram valine metabolism for the treatment of colorectal cancer
复制标题
靶向 HIBCH 重新编程缬氨酸代谢以治疗结直肠癌
DOI：
10.1038/s41419-019-1832-6
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发表时间：
2019-08-13
影响因子：
9
通讯作者：
Xu, Qiang
中科院分区：
文献类型：
--
作者：
Shan, Yunlong;Gao, Yuan;Xu, Qiang
已知缬氨酸分解代谢对于癌细胞至关重要，但详细机制仍不清楚。本研究旨在探讨 3-羟基异丁酰辅酶 A 水解酶 (HIBCH) 在结直肠癌 (CRC) 中的关键作用，并开发一种恢复缬氨酸代谢稳态的新疗法。 HIBCH 高表达首先被证实与 CRC 患者的不良生存相关，随后又与 CRC 细胞中细胞生长增加、细胞凋亡抵抗和自噬减少相关。 HIBCH 在 CRC 中的功能取决于其线粒体定位。进一步证明高HIBCH水平可以促进CRC细胞中三羧酸循环的代谢以及氧化磷酸化。基于上述发现，我们进一步发现了一种新型缬氨酸分解代谢抑制剂SBF-1。 SBF-1 对 HIBCH 线粒体定位的药理学阻断导致癌细胞生长减少和自噬增加，共同促进了体外和体内的抗肿瘤作用。此外，使用贝伐珠单抗进行抗 VEGF 治疗会增加 CRC 细胞中的 HIBCH 水平，进而导致对治疗的抵抗。 SBF-1 对 HIBCH 功能的干扰显着提高了贝伐珠单抗的抗肿瘤功效，并带来了强大的生存获益。本研究确定 HIBCH 是 CRC 进展和抗 VEGF 治疗耐药中缬氨酸分解代谢的关键酶。我们还提供了一种新型 HIBCH 抑制剂 SBF-1，强调使用缬氨酸分解代谢抑制剂与抗 VEGF 药物的联合治疗来控制 CRC 的进展。
Valine catabolism is known to be essential for cancer cells but the detailed mechanism remains unclear. This study is to explore the critical roles of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) in colorectal cancers (CRC) and to develop a new therapy returning valine metabolism homeostasis. High HIBCH expression was first confirmed to correlate with poor survival in patients with CRC, which was then linked to the increased cell growth, resistant apoptosis, and decreased autophagy in CRC cells. The functions of HIBCH in CRC were dependent on its mitochondrial localization. High HIBCH level was further demonstrated to promote the metabolism of tricarboxylic acid cycle as well as oxidative phosphorylation in CRC cells. Based on above findings, we further discovered a novel valine catabolism inhibitor SBF-1. The pharmacological blockade of HIBCH mitochondrial localization with SBF-1 resulted in decreased cancer cell growth and increased autophagy, collectively contributing to the antitumor effect both in vitro and in vivo. Moreover, anti-VEGF therapy with bevacizumab increased HIBCH level in CRC cells, which in turn caused the resistance to the therapy. The interference with HIBCH function by SBF-1 significantly increased the antitumor efficacy of bevacizumab and led to a robust survival benefit. The present study identified HIBCH as a critical enzyme of valine catabolism in CRC progression and resistance to anti-VEGF therapy. We also provided a novel HIBCH inhibitor SBF-1, which highlighted the combined therapy using valine catabolic inhibitor along with anti-VEGF drugs, to control progression of CRC.