DADS通过调控糖代谢重编程抑制结肠癌细胞生长与转移的机制研究

In colon cancer patients, tumor recurrence and metastasis are the leading cause of treatment failure. Therefore, it is urgent to figure out the underlying mechanisms of recurrence and metastasis, and investigate potential molecular-targeting drugs to improve the treatment outcome. Since metabolism reprogramming has remarkably core effect in boosting tumor growth, disturbing the metabolic reprogramming might be a novel anti-tumor strategy in colon cancer treatment. We have discovered that diallyl disulfide (DADS), a main active component of allicin, inhibits Rac1-mediated invasive migration in colon cancer. Rac1 has been shown to be involved into glycometabolism in colon cancer cells. Besides Rac1, DADS also regulates the expression of OCT1 (transcription factor of key glycolytic enzyme) and MM1 (ubiquitin degrading enzymes of c-myc), which suggests an important role of DADS in tumor metabolism reprogramming. However, the precise regulating pathways and involved molecules are still uncovered. According to related publications and our preliminary results, we hypothesize that DADS controls glycol-metabolism reprogramming and reduce DNA repair ability via regulating Rac1/OCT1/MM1 pathways and inhibiting c-myc / ALDOA (a key glycolytic enzyme) expressions. Such regulation and inhibition eventually contribute to growth suppression and metastasis inhibition in colon cancer cells. In summary, this study aims to illuminate the effect of DADS on glucose metabolism reprogramming in colon cancer cells and its underlying molecular mechanisms, and we also aim to provide experimental evidence for clinical use of DADS and to provide a new target for anti-cancer treatment in colon cancer from a metabolic perspective.

复发和转移是制约结肠癌疗效的瓶颈，急需深入揭示其机制并针对性开发分子靶向药物。现认为肿瘤代谢重编程是肿瘤生长的核心，干扰代谢重编程是抗肿瘤治疗新策略。我们发现DADS(大蒜素的主要有效成分)可抑制Rac1介导的结肠癌侵袭迁移，Rac1可影响结肠癌细胞糖代谢；还发现DADS可影响OCT1 (糖酵解关键酶转录因子)、MM1(泛素化降解c-Myc)等代谢重编程相关基因的表达，提示DADS可调控肿瘤代谢重编程，但机制不清。基于文献报道和我们初步结果，提出科学假说：DADS通过下调Rac1/OCT1、上调MM1抑制c-Myc、ALDOA(糖酵解关键酶)等分子的表达，进而调控糖代谢重编程并减弱DNA修复能力，最终抑制结肠癌细胞生长和转移。项目将阐明DADS调控肿瘤细胞糖代谢重编程的作用与机制，拓展DADS抗肿瘤作用机制的认识，为临床开发应用DADS提供实验证据，也从代谢角度为结肠癌临床治疗提供新靶点。

复发和转移是制约结肠癌疗效的瓶颈，急需深入揭示其机制并针对性开发分子靶向药物。研究认为肿瘤代谢重编程是肿瘤生长的核心，干扰代谢重编程可为抗肿瘤治疗提供新的策略。前期我们发现大蒜素的主要有效成分(DADS)可显著抑制结肠癌侵袭迁移，DADS可影响POU2F1 (又称OCT1, 是糖酵解关键酶转录因子)、MM1(泛素化降解c-Myc)等代谢重编程相关基因的表达，提示DADS可调控结肠癌细胞的糖代谢重编程，但其作用和机制有待明确。基于我们前期结果和文献报道，重点探讨了DADS是否以POU2F1为节点分子，并通过下调POU2F1调控结肠癌细胞糖代谢重编程和DNA修复能力，最终抑制结肠癌细胞生长和转移。结果显示：POU2F1在结肠癌组织中高表达并与结肠癌的不良预后正相关；POU2F1可通过减弱细胞内氧化应激诱导的DNA损伤抑制结肠癌细胞的凋亡；POU2F1可增强结肠癌细胞糖酵解和磷酸戊糖途径（PPP）的激活，其机制与POU2F1直接转录调控ALDOA（醛缩酶A）表达有关；DADS可通过下调POU2F1的表达显著抑制结肠癌细胞糖代谢重编程和PPP的激活，进一步研究发现，DADS可通过上调TRIM21来促进POU2F1 K272位点的泛素化降解，进而下调POU2F1的表达并调控结肠癌代谢重编程，最终抑制结肠癌细胞生长和转移。项目研究结果不仅阐明DADS、POU2F1调控肿瘤细胞糖代谢重编程的作用与机制，拓展DADS抗肿瘤作用机制的认识，为临床开发应用DADS提供实验证据，而且也从代谢角度为结肠癌临床治疗提供了新靶点。