PKC Beta II: A target for colon cancer chemoprevention

描述(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确定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，我们已将蛋白激酶C BII(PKCB11)确定为治疗干预的潜在靶点。PKCB11在结肠癌发生的早期就被诱导。在结肠上皮细胞中过表达PKCB11的转基因小鼠表现出结肠的过度增殖和对致癌物诱导的结肠癌的易感性增加。相比之下，PKCB基因敲除(PKCBKO)小鼠对结肠癌的发生具有极强的抵抗力，只有在结肠上皮细胞中重新表达PKCB11才能恢复癌症的敏感性。PKCB11刺激RAS-“PKC1/rac1-”MEK和Wnt/APC/B-catenin通路的信号传导，这两条信号通路在结肠癌中经常失控。PKCB11还可诱导COX-2表达，抑制转化生长因子-β信号转导。化学预防饮食w-3脂肪酸抑制结肠癌的发生，至少部分是通过直接抑制PKCB11介导的信号传导。这一数据表明，PKCBll在结肠癌的发生中起着关键的促进作用，并表明PKCBll是结肠癌化学预防的一个有吸引力的靶点。由于PKCB11在结肠癌发生中起关键作用，我们推测PKCB的选择性抑制剂LY317615将在小鼠结肠癌发生模型中显示出有效的化学预防活性。这一假设将通过完成两个特定目标来验证，这两个目标将确定LY317615对1)PKCB11介导的基因表达、信号和体内细胞动态平衡的影响，以及2)在临床前小鼠模型中诱导结肠癌的发生。本提案中描述的实验的成功完成将为在高危患者人群中使用PKCB抑制剂进行结肠癌的化学预防提供有价值的临床前支持。

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.