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，我们已经鉴定了蛋白激酶C BII（PKCBII）作为治疗干预的潜在靶标。PKCB 11在结肠癌发生过程中早期被诱导。在结肠上皮中过表达PKCB 11的转基因小鼠表现出结肠过度增殖和对致癌物诱导的结肠癌发生的易感性增加。相比之下，PKCB敲除（PKCBKO）小鼠对结肠癌发生具有极强的抗性，并且仅在结肠上皮中PKCBII的再表达恢复了癌症易感性。PKCB 11刺激Ras-“PKC 1/Rac 1-“MEK和Wnt/APC/B-连环蛋白途径的信号传导，这两种信号传导途径在结肠癌中经常失调。PKCB 11还诱导考克斯-2表达并抑制TGF-β信号传导。化学预防膳食w-3脂肪酸至少部分地通过直接抑制PKCBII介导的信号传导来抑制结肠癌发生。该数据表明PKCB 11在结肠癌发生中起关键的促进作用，并指出PKCB 11是结肠癌化学预防的有吸引力的靶标。由于PKCB 11在结肠癌发生中起关键作用，我们假设PKCB的选择性抑制剂LY 317615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。将通过完成2个特定目的来测试该假设，所述特定目的将确定LY 317615对1）体内PKCBII介导的基因表达、信号传导和细胞稳态以及2）临床前小鼠模型中结肠癌发生的诱导的影响。成功完成本提案中描述的实验将为PKCB抑制剂在高危患者人群中结肠癌的化学预防中的应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.