PKC Beta II: A target for colon cancer chemoprevention

PKC Beta II：结肠癌化学预防的靶点

• 批准号: 7003620
• 负责人: Nicole R Murray
• 金额: $ 7.5万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7003620
• 关键词: carcinogenesis inhibitor; cell growth regulation; chemoprevention; colon neoplasms; dosage; drug screening /evaluation; gene expression; genetically modified animals; kinase inhibitor; laboratory mouse; protein kinase C

DESCRIPTION (provided by applicant): Colon cancer is the second leading cause of cancer death in the United States. Our long-term goal is to reduce the impact of colon cancer through the identification and characterization of relevant targets for chemopreventive and chemotherapeutic drugs. To this end, we have identified protein kinase C BII (PKCBll) as a potential target for therapeutic intervention. PKCBll is induced early during colon carcinogenesis. Transgenic mice overexpressing PKCBll in the colonic epithelium exhibit colonic hyperproliferation and increased susceptibility to carcinogen-induced colon carcinogenesis. In contrast, PKCB knockout (PKCBKO) mice are extremely resistant to colon carcinogenesis and re-expression of PKCBll only in the colonic epithelium restores cancer susceptibility. PKCBll stimulates signaling of the Ras-"PKC1/Rac1 -"MEK and Wnt/APC/B-catenin pathways, 2 signaling pathways frequently disregulated in colon cancer. PKCBll also induces Cox-2 expression and suppresses TGF-B signaling. Chemopreventive dietary w-3 fatty acids inhibit colon carcinogenesis, at least in part, through direct inhibition of PKCBll-mediated signaling. This data demonstrates that PKCBll plays a critical, promotive role in colon carcinogenesis and point to PKCBll as an attractive target for the chemoprevention of colon cancer. Because of the critical role of PKCBll plays in colon carcinogenesis, we hypothesize that LY317615, a selective inhibitor of PKCB, will exhibit potent chemopreventive activity in a mouse model of colon carcinogenesis. This hypothesis will be tested through completion of 2 Specific Aims that will determine the effect of LY317615 on 1) PKCBll-mediated gene expression, signaling and cellular homeostasis in vivo and 2) induction of colon carcinogenesis in a preclinical mouse model. Successful completion of the experiments described in this proposal will provide valuable preclinical support for the use of PKCB inhibitors in the chemoprevention of colon cancer in high-risk patient populations.

描述（由申请人提供）：结肠癌是美国癌症死亡的第二大原因。我们的长期目标是通过识别和表征化学预防和化疗药物的相关靶点来减少结肠癌的影响。为此，我们确定蛋白激酶 C BII (PKCBll) 作为治疗干预的潜在靶点。 PKCB11在结肠癌发生的早期被诱导。在结肠上皮中过度表达PKCB11的转基因小鼠表现出结肠过度增殖并且对致癌物诱导的结肠癌发生的易感性增加。相反，PKCB敲除(PKCBKO)小鼠对结肠癌发生具有极强的抵抗力，并且仅在结肠上皮中重新表达PKCBll才能恢复癌症易感性。 PKCBll刺激Ras-“PKC1/Rac1-”MEK和Wnt/APC/B-连环蛋白途径的信号传导，这2种信号传导途径在结肠癌中经常失调。 PKCB11还诱导Cox-2表达并抑制TGF-B信号传导。化学预防性膳食 w-3 脂肪酸至少部分通过直接抑制 PKCBll 介导的信号传导来抑制结肠癌发生。该数据证明PKCB11在结肠癌发生中发挥关键的促进作用，并表明PKCB11作为结肠癌化学预防的有吸引力的靶标。由于PKCBll在结肠癌发生中发挥关键作用，我们假设PKCB的选择性抑制剂LY317615将在结肠癌发生的小鼠模型中表现出有效的化学预防活性。该假设将通过完成 2 个具体目标进行测试，这些目标将确定 LY317615 对 1) PKCBll 介导的体内基因表达、信号传导和细胞稳态的影响，以及 2) 在临床前小鼠模型中诱导结肠癌发生的影响。本提案中描述的实验的成功完成将为 PKCB 抑制剂在高危患者人群结肠癌的化学预防中的使用提供宝贵的临床前支持。