ACSS3/PLIN3下调瘤内脂质堆积抑制前列腺癌新型内分泌治疗耐受的机制和功能研究

研究证实前列腺癌中异常堆积的脂质是肿瘤内雄激素合成的前体，是去势抵抗性前列腺癌（CRPC）转化和新型内分泌治疗（NET）耐受的关键因素。减少肿瘤细胞内堆积脂质，从源头上祛除肿瘤内来源的雄激素，其研究国内外尚未展开。脂滴包被蛋白PLIN3参与脂质代谢，并通过增强脂滴稳定性促进肿瘤细胞中的脂质堆积。申请者前期研究发现：PLIN3在前列腺癌组织中显著上调，并和脂质代谢相关分子ACSS3高度负相关；ACSS3通过抑制PLIN3减少肿瘤细胞内脂质堆积和雄激素合成；ACSS3抑制CRPC转化和NET耐受。据此提出“ACSS3/PLIN3下调肿瘤内脂质堆积是抑制CRPC转化和NET耐受的关键信号通路”假说。本项目以NET耐受的CRPC细胞和动物模型为研究对象，通过多种分子生物学实验探讨ACSS3/PLIN3通路在CRPC治疗中的作用和调控机理，以验证该假说，为前列腺癌临床治疗提供新的治疗靶点和研究思路。

Abnormal lipids accumulation，as the precursors of androgen synthesis in tumor cells, are the key factors in the castration-resistant prostate cancer (CRPC) progression and its new endocrine therapy (NET) resistance. How to eliminate the lipid accumulation in tumor cells and reduce the androgen derived from tumors at the source has not been studied yet. The lipid droplet coating protein 3 (PLIN3) is involved in lipid metabolism and can promote lipid accumulation in tumor cells by increasing the stability of lipid droplets. Our previous studies found that PLIN3 was highly expressed during the prostate cancer progression. The lipid metabolism-related molecule gene ACSS3 can reduce the lipid accumulation and androgen levels in tumor cells by inhibiting PLIN3 expression. Based on these results, we proposed the hypothesis that: ACSS3/PLIN3-mediated lipid elimination is a key pathway that inhibits the CRPC progression and reverses the NET resistance. This project focuses on CRPC cells and animal models which resistant to NET, and demonstrates the hypothesis that the functions and mechanisms of ACSS3/PLIN3 pathway in the prostate cancer progression through a variety of molecular biological experiments. It provides the new therapeutic targets and research directions for clinical treatment of prostate cancer.