Shanghai University of Traditional Chinese Medicine, Shanghai 200082, P.R. China.
Department of Gastroenterology, Shanghai Traditional Chinese Medicine‑Integrated Hospital, Shanghai 200082, P.R. China.
Mol Med Rep. 2020 Aug;22(2):774-782. doi: 10.3892/mmr.2020.11151. Epub 2020 May 18.
Colorectal cancer is a digestive tract malignancy and the third leading cause of cancer‑related mortality worldwide. Norcantharidin (NCTD), the demethylated form of cantharidin, has been reported to possess anticancer properties. Family‑with‑sequence‑similarity‑46c (Fam46c), a non‑canonical poly(A) polymerase, has been reported to be critical in NCTD‑mediated effects in numerous types of cancer, including hepatoma. In the current study, it was found that Fam46c expression was reduced in colorectal cancer tissues and cells. Treatment with NCTD was observed to significantly enhance apoptosis and inhibit glycolysis in colorectal cancer cells. In addition, Fam46c and cleaved caspase 3 expression levels were found to be increased in response to NCTD treatment, in contrast to tumor‑specific pyruvate kinase M2 and phosphorylated ERK expression, which was reduced. Importantly, overexpression of Fam46c exerted similar effects as NCTD treatment on the apoptosis and glycolysis of colorectal cancer cells, whereas Fam46c knockdown strongly attenuated the effect of NCTD. Moreover, epidermal growth factor, which acts as an agonist of ERK1/2 signaling, weakened the effects of NCTD on colorectal cancer cells. Taken together, the results indicated that NCTD promotes apoptosis and suppresses glycolysis in colorectal cancer cells by possibly targeting Fam46c and inhibiting ERK1/2 signaling, hence suggesting that Fam46c may act as a tumor suppressor in colorectal cancer. Thus, the present study identified a novel therapeutic target of NCTD in the clinical treatment of colorectal cancer.
结直肠癌是一种消化道恶性肿瘤，也是全球癌症相关死亡的第三大主要原因。去甲基斑蝥素（NCTD）是斑蝥素的去甲基形式，据报道具有抗癌特性。家族与序列相似性 46c（Fam46c）是一种非典型的多聚（A）聚合酶，据报道在包括肝癌在内的多种类型的癌症中，NCTD 介导的作用中起着关键作用。在本研究中，发现 Fam46c 在结直肠癌组织和细胞中的表达降低。用 NCTD 处理观察到结直肠癌细胞凋亡显著增强，糖酵解受到抑制。此外，与肿瘤特异性丙酮酸激酶 M2 和磷酸化 ERK 的表达降低相反，发现 Fam46c 和裂解的 caspase 3 的表达水平在 NCTD 处理后增加。重要的是， Fam46c 的过表达对结直肠癌细胞的凋亡和糖酵解产生与 NCTD 处理相似的作用，而 Fam46c 的敲低则强烈减弱了 NCTD 的作用。此外，作为 ERK1/2 信号激动剂的表皮生长因子削弱了 NCTD 对结直肠癌细胞的作用。总之，这些结果表明，NCTD 通过可能靶向 Fam46c 并抑制 ERK1/2 信号来促进结直肠癌细胞凋亡和抑制糖酵解，因此表明 Fam46c 可能在结直肠癌中作为肿瘤抑制因子发挥作用。因此，本研究确定了 NCTD 在结直肠癌临床治疗中的一个新的治疗靶点。
