The role of GSTP1 in oncogenic K-Ras signaling

GSTP1 在致癌 K-Ras 信号传导中的作用

• 批准号: 7383927
• 负责人: DUYEN DANG
• 金额: $ 14.78万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7383927
• 关键词: Antineoplastic Agents; Antioxidants; Apoptosis; Biological; Cancer cell line; Cell Line; Cells; Clinical; Colon Carcinoma; Colorectal Cancer; Condition; Data; Dependence; Drug Metabolic Detoxication; Enzymes; Genetic Status; Glutathione S-Transferase; Growth; HCT116 Cells; Heel; Human; MEKs; Mediating; Mutate; Mutation; Oncogenic; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Protein Overexpression; Proto-Oncogenes; Reporting; Role; Series; Signal Transduction; Stress; Testing; Tumor Markers; Tumorigenicity; cancer cell; in vivo; interest; member; therapeutic target

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.

结肠癌是通过突变的逐步积累而发展的。最早的一 在K-RAS原癌基因中发生转化突变。为了开发有效的抗癌药物， 重要的是阐明致癌K-RAS的效应。致癌K-RAS信号传导的两种已知效应物 是MEK/ERK和细胞氧化还原途径。最近发现，致癌K-RAS与 谷胱甘肽S-转移酶pi 1（GSTP 1）在结肠癌中的过度表达。生物 这种关联的意义尚不清楚。 谷胱甘肽S-转移酶超家族成员GSTP 1广泛过表达 在结肠癌中。已知GSTP 1具有抗氧化、解毒和应激信号传导功能。因此，在本发明中， 对GST P1作为肿瘤标记物和治疗靶点的临床兴趣相当大。 该提案中的初步数据表明，致癌K- RAS决定细胞对GST 1的依赖性。这一观察的机制是 未知最近，我们的实验室报道GSTP 1促进MEK/ERK激活并保护 生长限制条件下的氧化应激。这些观察结果导致了这样的假设， GSTP 1通过维持MEK/ERK活化和细胞增殖促进有效的致癌K-RAS信号传导 氧化还原本文提出了三个具体的目标来验证上述假设：（1）确定机制 GST P1介导MEK和ERK的致癌性K-RAS激活，（2）为了确定GST P1在K-RAS激活过程中的作用， GST P1降低致癌K-RAS产生的氧化应激的机制，和（3） 确定GST P1在致癌K-RAS促进的体内致瘤性中的作用。 该提议探讨了一个悖论，即虽然致癌K-RAS赋予有丝分裂优势， 在生长限制条件下的癌细胞，它无意中使细胞依赖于GSTP 1。作为 因此，携带致癌K-RAS的结肠癌可能存在潜在的“阿喀琉斯之踵”：它们更多 依赖于生长限制条件下的GSTP 1表达。这种致癌依赖性可能 最终可用于结肠直肠癌的治疗。