PRIMA-1met（APR-246）诱导不同状态P53基因的结直肠癌细胞自噬及其相关机制的研究

Colorectal cancer (CRC) is one of the most common malignancies with high morbidity and mortality, asking for more efficient therapies. P53 as a tumor suppressor gene is hot in cancer research. P53 mutation occurs in about 40-50% CRC cases, which is closely associated with progression of tumor. PRIMA-1met, a methylated derivative and structural analog of PRIMA-1 (p53 re-activation and induction of massive apoptosis), restores specific DNA binding region to recover normal wild-type function to induce apoptosis in cancer cells. In our previous experiments, PRIMA-1met inhibited cell growth in CRC cells with different P53 status. However, the ability to induce apoptosis performed significant differences among them. We suppose that PRIMA-1met not only promotes apoptosis in CRC cells, but also exerts growth inhibition through other mechanisms. In this project, we want to prove the autophagy induction of PRIMA-1met in CRC cells and its deep molecule mechanism to make sure that whether dependently on P53 status. On the other hand, we will investigate the influence of abnormal expression in apoptotic pathway by PRIMA-1met on its autophagy induction. Further, combined with previous results, we will discuss the cell growth inhibition in CRC cells carrying different P53 by PRIMA-1met definitely. PRIMA-1met will be demonstrated to have great potential as a new therapeutic agent.

结直肠癌是临床常见的恶性肿瘤，需寻求更为有效的治疗手段及药物。P53作为重要的抑癌基因，是肿瘤治疗研究领域的热点。约有40-50%的结直肠癌病例存在该基因的突变，与肿瘤的发生发展密切相关。PRIMA-1met是一种新型小分子物质，能使发生突变的p53蛋白特定序列DNA结合区的结构改变进而恢复诱导肿瘤细胞凋亡的功能。前期实验发现，PRIMA-1met可以抑制不同状态P53基因的结直肠癌细胞生长，但其促凋亡作用存在一定差异。我们推测PRIMA-1met不仅可以促进结直肠癌细胞凋亡，还可通过其它一些机制发挥抑制生长的作用。本项目拟通过体外实验证实PRIMA-1met可以诱导结直肠癌细胞自噬的发生，并论证其与细胞所携带的P53基因状态的相关性，明确相关分子机制。并探讨PRIMA-1met诱导结直肠癌细胞凋亡通路分子的异常表达对诱导自噬的影响。为PRIMA-1met用于结直肠癌治疗提供基础研究依据。