The role of GSTP1 in oncogenic K-Ras signaling

结肠癌是通过突变的逐步积累发展起来的。世界上最早的 K-RAS原癌基因发生非转化突变。为了开发有效的抗癌药物，它是 对阐明致癌K-RAS的效应因子具有重要意义。致癌K-RAS信号的两个已知效应因子 有MEK/ERK和细胞氧化还原途径。最近发现致癌的K-RAS与肿瘤密切相关 结肠癌组织中谷胱甘肽S转移酶PI1的过度表达。生物学的 这种联系的意义尚不清楚。 谷胱甘肽转移酶1是谷胱甘肽S转移酶超家族的成员，广泛过表达 结肠癌。GSTP1具有已知的抗氧化、解毒和应激信号功能。因此， GSTP1作为一种肿瘤标记物和治疗靶点已经引起了相当大的临床兴趣。 这项建议中的初步数据表明，致癌K-的存在或不存在 RAS决定细胞对GSTP1的依赖性。这种观察结果背后的机制是 未知。最近，我们的实验室报道了GSTP1促进MEK/ERK激活并保护其免受病毒感染。 生长受限条件下的氧化应激。这些观察结果导致了这样一种假设 GSTP1通过维持MEK/ERK激活和细胞外信号转导促进有效的致癌K-RAS信号转导 氧化还原。提出了三个具体目标来检验上述假说：(1)确定机制 通过GSTP1介导MEK和ERK的致癌K-RAS活化，(2)确定 GSTP1降低致癌K-RAS产生的氧化应激的机制，以及(3) 确定GSTP1在K-RAS促进的体内致瘤性中的作用。 这项建议探索了一个悖论，即虽然致癌的K-RAS赋予有丝分裂的优势 作为生长受限条件下的癌细胞，它在不经意间使细胞依赖GSTP1。AS 这种潜在的“跟腱”可能存在于携带致癌K-RAS的结肠癌中：它们比 依赖于生长限制条件下GSTP1的表达。这种致癌依赖可能 最终可用于结直肠癌的治疗。

Colon cancer develops through the stepwise accumulation of mutations. One of the earliest iransforming mutations occurs in the K-RAS proto-oncogene. To develop effective anticancer agents, it is mportant to elucidate effectors of oncogenic K-RAS. Two known effectors of oncogenic K-RAS signaling are MEK/ERK and cellular redox pathways. Recently, oncogenic K-RAS was found to be closely associated with the overexpression of glutathione S-transferase pi1 (GSTP1) in colon cancer. The biological significance of this association remains unclear. GSTP1, a member of the glutathione S-transferase enzyme superfamily, is widely overexpressed in colon cancer. GSTP1 has known antioxidant, detoxification, and stress signaling functions. As such, there has been considerable clinical interest in GSTP1 as a tumor marker and as a therapeutic target. The preliminary data in this proposal demonstrate that the presence or absence of oncogenic K- RAS determines cellular dependence on GSTP1. The mechanisms that underlie this observation are unknown. Recently, our lab reported that GSTP1 promotes MEK/ERK activation and protects against oxidative stress under growth-limiting conditions. These observations have led to the hypothesis that GSTP1 facilitates effective oncogenic K-RAS signaling by maintaining MEK/ERK activation and cellular redox. Three specific aims are proposed to test the above hypothesis: (1) To determine the mechanisms by which GSTP1 mediates oncogenic K-RAS activation of MEK and ERK, (2) To determine the mechanisms by which GSTP1 reduces oxidative stress generated by oncogenic K-RAS, and (3) To determine the role of GSTP1 in oncogenic K-RAS-promoted tumorigenicity in vivo. This proposal explores the paradox that while oncogenic K-RAS confers a mitogenic advantage to a cancer cell under growth-limiting conditions, it inadvertently renders the cell dependent on GSTP1. As such, a potential "Achilles Heel" may exist in colon cancers that harbor oncogenic K-RAS: they are more dependent on GSTP1 expression under growth-limiting conditions. This oncogenic dependence may eventually be exploitable for the therapy of colorectal cancer.