Targeting Atg5 in platinum-resistant ovarian cancer

靶向 Atg5 治疗铂耐药卵巢癌

• 批准号: 10307116
• 负责人: GEN SHENG WU
• 金额: $ 21.17万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307116
• 关键词: Address; Apoptosis; Autophagocytosis; Autophagosome; Cancer Etiology; Cancer Patient; Carboplatin; Cell Survival; Cells; Cessation of life; Chemoresistance; Cisplatin; Clinical; Complex; Data; Development; Disease; Drug resistance; Epithelial; Gene Family; Genes; Goals; Growth; Half-Life; Human; In Vitro; Lead; Malignant neoplasm of ovary; Mediating; Nutrient; Outcome; Ovarian Tissue; Patients; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Platinum; Play; Process; Proteins; Public Health; Quality Control; Regulation; Relapse; Research; Resistance; Role; Stress; Structure; Testing; Therapeutic Intervention; Treatment Failure; United States; Work; base; cancer cell; cancer therapy; chemotherapy; drug development; improved; in vivo; inhibition of autophagy; innovation; member; mouse model; new therapeutic target; novel; novel therapeutic intervention; ovarian neoplasm; overexpression; response

Abstract Ovarian cancer is the fifth leading cause of cancer-related death in the United States. The standard first line chemotherapy to treat this deadly disease includes platinum (cisplatin/carboplatin)-based treatment, but the development of drug resistance presents a significant clinical problem that needs to be addressed. Our current study identifies a novel mechanism of cisplatin resistance involving autophagy-related gene (Atg) 5. Atg5 is a member of the Atg family that plays an important role in regulating autophagy, a process essential for the quality control of cellular components under various stress conditions. Previous studies showed that the inhibition of autophagy sensitizes cancer cells to chemotherapy. Our own study showed that the blockade of autophagy induction promotes cisplatin sensitivity in human ovarian cancer cells, but strategies for targeting autophagy in cancer therapies in general are not well developed. We find that Atg5 is overexpressed in human ovarian tumors, and that its overexpression inhibits cisplatin-induced apoptosis in ovarian cancer cells. We also find that Atg5 overexpression is correlated with the poor overall survival in ovarian cancer patients treated with platinum-based chemotherapy. Additionally, we find that Atg5 is phosphorylated but the effects of its phosphorylation on Atg5-mediated autophagy and cisplatin resistance remain to be determined. Based on these novel observations, we hypothesize that elevated Atg5 expression confers growth advantage of ovarian cancer cells by promoting cell survival and drug resistance. The objectives of this project are to define the role of Atg5 in cisplatin resistance and the impact of Atg5 phosphorylation on cisplatin resistance. These objectives will be achieved by the following two Specific Aims: 1) Define the role of Atg5 in cisplatin resistance both in vitro and in vivo using ovarian cancer mouse models; and 2) Determine the regulation of Atg5 phosphorylation and its impact on cisplatin resistance. Successful results from this study could lead to the development of novel therapeutic strategies for treating ovarian cancer patients.

摘要 卵巢癌是美国癌症相关死亡的第五大原因。的标准第一 治疗这种致命疾病的线化疗包括基于铂（顺铂/卡铂）的治疗， 但是耐药性的发展提出了需要解决的重要临床问题。 我们目前的研究发现了一种新的顺铂耐药机制，涉及自噬相关基因 (Atg)五、 Atg 5是Atg家族的一员，在调节自噬中起重要作用，自噬是一个过程， 对于在各种应力条件下的细胞组分的质量控制至关重要。以前的研究 自噬的抑制使癌细胞对化疗敏感。我们自己的研究表明 自噬诱导的阻断促进了人卵巢癌细胞中顺铂的敏感性，但是 在癌症治疗中靶向自噬的策略通常没有得到很好的开发。我们发现Atg 5 在人卵巢肿瘤中过表达，并且其过表达抑制顺铂诱导的卵巢癌。 卵巢癌细胞凋亡。我们还发现，Atg 5过表达与总体不良相关。 以铂类为基础的化疗治疗卵巢癌患者的生存率。此外，我们发现， Atg 5是磷酸化的，但其磷酸化对Atg 5介导的自噬和顺铂的影响是不确定的。 阻力仍有待确定。基于这些新的观察结果，我们假设升高的Atg 5 表达通过促进细胞存活和药物治疗赋予卵巢癌细胞生长优势 阻力本项目的目的是确定Atg 5在顺铂耐药中的作用，以及Atg 5在顺铂耐药中的作用。 Atg 5磷酸化对顺铂耐药性影响。这些目标将通过以下方式实现： 两个具体目的：1）使用卵巢癌细胞系，在体外和体内确定Atg 5在顺铂抗性中的作用。 癌症小鼠模型;和2）确定Atg 5磷酸化的调节及其对肿瘤的影响。 顺铂耐药。 这项研究的成功结果可能会导致新的治疗策略的发展， 治疗卵巢癌患者。