Both the MAPK pathway and mevalonate (MVA) signaling pathway play an increasingly significant role in the carcinogenesis of colorectal carcinoma, whereas the cross-talk between these two pathways and its implication in targeted therapy remains unclear in colorectal carcinoma. Here, we identified that HMGCS1 (3-hydroxy-3-methylglutaryl-CoA synthase 1), the rate-limiting enzyme of the MVA pathway, is overexpressed in colon cancer tissues and positively regulates the cell proliferation, migration, and invasion of colon cancer cells. In addition, HMGCS1 could enhance the activity of pERK independent of the MVA pathway, and the suppression of HMGCS1 could completely reduce the EGF-induced proliferation of colon cancer cells. Furthermore, we found that trametinib, a MEK inhibitor, could only partially abolish the upregulation of HMGCS1 induced by EGF treatment, while combination with HMGCS1 knockdown could completely reverse the upregulation of HMGCS1 induced by EGF treatment and increase the sensitivity of colon cancer cells to trametinib. Finally, we combined trametinib and dipyridamole, a common clinically used drug that could suppress the activity of SREBF2 (sterol regulatory element-binding transcription factor 2), a transcription factor regulating HMGCS1 expression, and identified its synergistic effect in inhibiting the proliferation and survival of colon cancer cells in vitro as well as the in vivo tumorigenic potential of colon cancer cells. Together, the current data indicated that HMGCS1 may be a novel biomarker, and the combination of targeting HMGCS1 and MEK might be a promising therapeutic strategy for patients with colon cancer.

中文翻译：

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双嘧达莫通过联合靶向 HMGCS1 和 MEK 通路增强曲美替尼对结肠癌细胞的细胞毒性

MAPK 通路和甲羟戊酸 (MVA) 信号通路在结直肠癌的癌变中发挥越来越重要的作用，而这两条通路之间的相互作用及其在靶向治疗中的意义在结直肠癌中仍不清楚。在这里，我们发现 HMGCS1（3-羟基-3-甲基戊二酰辅酶 A 合酶 1）是 MVA 途径的限速酶，在结肠癌组织中过表达，并正向调节结肠癌的细胞增殖、迁移和侵袭细胞。此外，HMGCS1可以独立于MVA途径增强pERK的活性，抑制HMGCS1可以完全降低EGF诱导的结肠癌细胞增殖。此外，我们发现曲美替尼，一种 MEK 抑制剂，只能部分消除 EGF 治疗诱导的 HMGCS1 上调，而结合 HMGCS1 敲低可以完全逆转 EGF 治疗诱导的 HMGCS1 上调，增加结肠癌细胞对曲美替尼的敏感性。最后，我们将曲美替尼和双嘧达莫（一种临床常用的药物，可以抑制 SREBF2（甾醇调节元件结合转录因子 2），一种调节 HMGCS1 表达的转录因子的活性结合，并确定其在抑制增殖和存活方面的协同作用。体外结肠癌细胞以及结肠癌细胞的体内致瘤潜力。总之，目前的数据表明 HMGCS1 可能是一种新的生物标志物，