The role of GSTP1 in oncogenic K-Ras signaling

描述(申请人提供)：结肠癌是通过突变的逐步积累发展起来的。最早的转化突变之一发生在K-RAS原癌基因中。为了开发有效的抗癌药物，阐明致癌K-RAS的效应分子是非常重要的。已知的两个致癌K-RAS信号的效应者是MEK/ERK和细胞氧化还原途径。近年来发现，癌基因K-RAS与结肠癌组织中谷胱甘肽S转移酶PI1的过表达密切相关。这种联系的生物学意义尚不清楚。谷胱甘肽转移酶1是谷胱甘肽S转移酶超家族成员之一，在结肠癌中广泛过表达。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。该提案中的初步数据表明，致癌KRAS的存在或不存在决定了细胞对GSTP1的依赖。这一观察结果背后的机制尚不清楚。最近，我们的实验室报道，在生长受限的条件下，GSTP1促进MEK/ERK的激活并保护其免受氧化应激的影响。这些观察结果导致一种假设，即GSTP1通过维持MEK/ERK激活和细胞氧化还原来促进有效的致癌K-RAS信号转导。为了验证上述假说，我们提出了三个具体的目标：(1)确定GSTP1介导MEK和ERK的致癌K-RAS活化的机制；(2)确定GSTP1降低致癌K-RAS产生的氧化应激的机制；(3)确定GSTP1在致癌K-RAS促进的体内致瘤作用中的作用。这个建议探索了一个悖论，即虽然致癌的K-RAS在生长受限的条件下赋予癌细胞有丝分裂的优势，但它无意中使细胞依赖GSTP1。因此，携带致癌K-RAS基因的结肠癌可能存在潜在的“跟腱”：在生长受限的条件下，它们更依赖于GSTP1的表达。这种致癌依赖性最终可能被用于结直肠癌的治疗。

DESCRIPTION (provided by applicant): Colon cancer develops through the stepwise accumulation of mutations. One of the earliest transforming mutations occurs in the K-RAS proto-oncogene. To develop effective anticancer agents, it is important 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 KRAS 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.