PKC Beta II: A target for colon cancer chemoprevention

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鉴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，我们确定了蛋白激酶C BII （PKCBll）作为治疗干预的潜在靶点。pkcll在结肠癌发生早期被诱导。在结肠上皮中过表达pkcll的转基因小鼠表现出结肠过度增生和对致癌物诱导的结肠癌的易感性增加。相比之下，PKCB敲除（PKCBKO）小鼠对结肠癌的发生具有极强的抵抗力，仅在结肠上皮中重新表达PKCBll可恢复癌症易感性。PKCBll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调。PKCBll还诱导Cox-2表达并抑制TGF-B信号传导。化学预防饮食中的w-3脂肪酸至少在一定程度上通过直接抑制pkcbll介导的信号传导抑制结肠癌的发生。这些数据表明pkcll在结肠癌发生中起着关键的促进作用，并指出pkcll是结肠癌化学预防的一个有吸引力的靶点。由于PKCBll在结肠癌发生中的关键作用，我们假设PKCB的选择性抑制剂LY317615将在结肠癌小鼠模型中表现出有效的化学预防活性。这一假设将通过完成2个特异性目标来验证，这些目标将确定LY317615对pkcbll介导的基因表达、信号传导和体内细胞稳态的影响，以及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抑制剂在高危患者群体中结肠癌化学预防中的使用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.