Egusquiza-Alvarez Carlos Alejandro, Moreno-Londoño Angela Patricia, Alvarado-Ortiz Eduardo, Ramos-Godínez María Del Pilar, Sarabia-Sánchez Miguel Angel, Castañeda-Patlán María Cristina, Robles-Flores Martha
Departamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City 04510, Mexico.
Departamento de Microscopía Electrónica, Instituto Nacional de Cancerología, Secretaría de Salud, Mexico City 14080, Mexico.
Int J Mol Sci. 2024 Feb 27;25(5):2712. doi: 10.3390/ijms25052712.
The protein p32 (C1QBP) is a multifunctional and multicompartmental homotrimer that is overexpressed in many cancer types, including colon cancer. High expression levels of C1QBP are negatively correlated with the survival of patients. Previously, we demonstrated that C1QBP is an essential promoter of migration, chemoresistance, clonogenic, and tumorigenic capacity in colon cancer cells. However, the mechanisms underlying these functions and the effects of specific C1QBP protein inhibitors remain unexplored. Here, we show that the specific pharmacological inhibition of C1QBP with the small molecule M36 significantly decreased the viability rate, clonogenic capacity, and proliferation rate of different colon cancer cell lines in a dose-dependent manner. The effects of the inhibitor of C1QBP were cytostatic and non-cytotoxic, inducing a decreased activation rate of critical pro-malignant and mitogenic cellular pathways such as Akt-mTOR and MAPK in RKO colon cancer cells. Additionally, treatment with M36 significantly affected the mitochondrial integrity and dynamics of malignant cells, indicating that p32/C1QBP plays an essential role in maintaining mitochondrial homeostasis. Altogether, our results reinforce that C1QBP is an important oncogene target and that M36 may be a promising therapeutic drug for the treatment of colon cancer.
蛋白质p32（C1QBP）是一种多功能且存在于多个细胞区室的同三聚体，在包括结肠癌在内的多种癌症类型中均有过表达。C1QBP的高表达水平与患者的生存率呈负相关。此前，我们证明C1QBP是结肠癌细胞迁移、化疗耐药性、克隆形成能力和致瘤能力的重要促进因子。然而，这些功能背后的机制以及特定C1QBP蛋白抑制剂的作用仍未得到探索。在此，我们表明，小分子M36对C1QBP的特异性药理抑制以剂量依赖的方式显著降低了不同结肠癌细胞系的存活率、克隆形成能力和增殖率。C1QBP抑制剂的作用具有细胞生长抑制性且无细胞毒性，可降低RKO结肠癌细胞中关键的促恶性和促有丝分裂细胞通路（如Akt - mTOR和MAPK）的激活率。此外，用M36处理显著影响了恶性细胞的线粒体完整性和动态变化，表明p32/C1QBP在维持线粒体稳态中起重要作用。总之，我们的结果强化了C1QBP是一个重要的癌基因靶点，且M36可能是一种有前景的治疗结肠癌的药物。
