PI3K/Akt通路阻断在恶性肿瘤治疗中的研究进展

在肺癌的发生发展过程中,常伴有PI3K/Akt信号通路的异常活化,过度激活后,可导致一系列反应,包括肿瘤牛长、血管生成、增殖和转移.本文拟就PI3K/Akt信号通路的组成与功能、调节、抗肿瘤细胞凋亡以及治疗等方面的研究进展作一综述,并就其通路的阻断作用在肺癌治疗中的应用作介绍,期待以PI3K/Akt信号通路中关键分子为...     

Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors

CONTEXT: As in many other human cancers, overactivation of the phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway occurs frequently in thyroid cancer, but the mechanism is not completely clear. OBJECTIVE: Because activating mutations and genomic amplification of the PIK3CA gene, which encodes the p110a catalytic subunit of PI3K, are common in many cancers, we sought to investigate this phenomenon in thyroid tumors. DESIGN: To search for PIK3CA mutations, we isolated genomic DNA from primary thyroid tumors of various types and performed direct sequencing of the exons of PIK3CA gene that carry the most common mutations in other cancers. We used real-time quantitative PCR to investigate genomic amplification of the PIK3CA gene. RESULTS: We found no PIK3CA gene mutations in 37 benign thyroid adenomas, 52 papillary thyroid cancers, 25 follicular thyroid cancers, 13 anaplastic thyroid cancers, 13 medullary thyroid cancers, and seven thyroid tumor cell lines. We found a C3075T single-nucleotide polymorphism in exon 20 of this gene in two cases. With a copy number of 4 or more defined as amplification, we found PIK3CA gene amplification in four of 34 (12%) benign thyroid adenomas, three of 59 (5%) papillary thyroid cancer, five of 21 (24%) follicular thyroid cancer, none of 14 (0%) medullary thyroid cancer, and five of seven (71%) thyroid tumor cell lines. The PIK3CA gene amplification and consequent Akt activation were confirmed by fluorescence in situ hybridization and Western blotting studies using cell lines, respectively. CONCLUSION: These data suggest that mutation of the PIK3CA gene is not common, but its amplification is relatively common and may be a novel mechanism in activating the PI3K/Akt pathway in some thyroid tumors.     

Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer

AIM: To investigate human epidermal growth factor receptor 2 (HER2)-phosphatidylinositol 3-kinase (PI3K)-v-Akt murine thymoma viral oncogene homolog signaling pathway.METHODS: We analyzed 231 formalin-fixed, paraffin-embedded gastric cancer tissue specimens from Japanese patients who had undergone surgical treatment. The patients’ age, sex, tumor location, depth of invasion, pathological type, lymph node metastasis, and pathological stage were determined by a review of the medical records. Expression of HER2 was analyzed by immunohistochemistry (IHC) using the HercepTest^TM kit. Standard criteria for HER2 positivity (0, 1+, 2+, and 3+) were used. Tumors that scored 3+ were considered HER2-positive. Expression of phospho Akt (pAkt) was also analyzed by IHC. Tumors were considered pAkt-positive when the percentage of positive tumor cells was 10% or more. PI3K, catalytic, alpha polypeptide (PIK3CA) mutations in exons 1, 9 and 20 were analyzed by pyrosequencing. Epstein-Barr virus (EBV) infection was analyzed by in situ hybridization targeting EBV-encoded small RNA (EBER) with an EBER-RNA probe. Microsatellite instability (MSI) was analyzed by polymerase chain reaction using the mononucleotide markers BAT25 and BAT26.RESULTS: HER2 expression levels of 0, 1+, 2+ and 3+ were found in 167 (72%), 32 (14%), 12 (5%) and 20 (8.7%) samples, respectively. HER2 overexpression (IHC 3+) significantly correlated with intestinal histological type (15/20 vs 98 /205, P = 0.05). PIK3CA mutations were present in 20 cases (8.7%) and significantly correlated with MSI (10/20 vs 9/211, P < 0.01). The mutation frequency was high (21%) in T4 cancers and very low (6%) in T2 cancers. Mutations in exons 1, 9 and 20 were detected in 5 (2%), 9 (4%) and 7 (3%) cases, respectively. Two new types of PIK3CA mutation, R88Q and R108H, were found in exon1. All PIK3CA mutations were heterozygous missense single-base substitutions, the most common being H1047R (6/20, 30%) in exon20. Eighteen cancers (8%) were EBV-positive and this positivity significantly correlated with a diffuse histological type (13/18 vs 93/198, P = 0.04). There were 7 cases of lymphoepithelioma-like carcinomas (LELC) and 6 of those cases were EBV-positive (percent/EBV: 6/18, 33%; percent/all LELC: 6/7, 86%). pAkt expression was positive in 119 (53%) cases but showed no correlation with clinicopathological characteristics. pAkt expression was significantly correlated with HER2 overexpression (16/20 vs 103/211, P < 0.01) but not with PIK3CA mutations (12/20 vs 107/211, P = 0.37) or EBV infection (8/18 vs 103/211, P = 0.69). The frequency of pAkt expression was higher in cancers with exon20 mutations (100%) than in those with exon1 (40%) or exon9 (56%) mutations. One case showed both HER2 overexpression and EBV infection and 3 cases showed both PIK3CA mutations and EBV infection. However, no cases showed both PIK3CA mutations and HER2 overexpression. One EBV-positive cancer with PIK3CA mutation (H1047R) was MSI-positive. Three of these 4 cases were positive for pAkt expression. In survival analysis, pAkt expression significantly correlated with a poor prognosis (hazard ratio 1.75; 95%CI: 1.12-2.80, P = 0.02).CONCLUSION: HER2 expression, PIK3CA mutations and EBV infection in gastric cancer were characterized. pAkt expression significantly correlates with HER2 expression and with a poor prognosis.     

Targeting the PI3K/Akt signaling pathway in gastric carcinoma: A reality for personalized medicine?

Frequent activation of phosphatidylinositol-3 kinases (PI3K)/Akt/mTOR signaling pathway in gastric cancer (GC) is gaining immense popularity with identification of mutations and/or amplifications of PIK3CA gene or loss of function of PTEN, a tumor suppressor protein, to name a few; both playing a crucial role in regulating this pathway. These aberrations result in dysregulation of this pathway eventually leading to gastric oncogenesis, hence, there is a need for targeted therapy for more effective anticancer treatment. Several inhibitors are currently in either preclinical or clinical stages for treatment of solid tumors like GC. With so many inhibitors under development, further studies on predictive biomarkers are needed to measure the specificity of any therapeutic intervention. Herein, we review the common dysregulation of PI3K/Akt/mTOR pathway in GC and the various types of single or dual pathway inhibitors under development that might have a superior role in GC treatment. We also summarize the recent developments in identification of predictive biomarkers and propose use of predictive biomarkers to facilitate more personalized cancer therapy with effective PI3K/Akt/mTOR pathway inhibition.     

磷脂酰肌醇3-激酶p110β在胃癌中的表达及其与预后的关系

目的:研究磷脂酰肌醇3-激酶(PI3K)p110β蛋白在胃癌组织中的表达,并探讨其与预后的关系。方法:收集本院1996至2001年59例胃癌患者手术标本,应用PI3Kp110β多克隆抗体免疫组织化学方法检测其不同类型胃癌组织及癌旁正常胃组织中PI3Kp110β的表达。采用生存分析法分析其与预后的关系。结果:在59例胃癌组织中,PI3Kp110β阳性表达47例;在正常胃组织中其阳性表达13例(P<0.01);且PI3Kp110β表达弱阳性患者其生存率也低于PI3Kp110β表达阴性患者(P<0.05)。结论:PI3Kp110β在低分化、浸润深及淋巴结转移的胃癌中高表达,PI3Kp110β的阳性表达对判断胃癌患者的预后有参考价值。     

PI3K/AKT信号通路在RANKL诱导的SGC-7901胃癌细胞迁移中的作用

目的文献报道RANKL/RANK/OPG途径与肿瘤细胞迁移及骨转移密切相关,但RANKL/RANK途径是否参与胃癌细胞迁移,尚无文献报道。本文拟检测RANK在胃癌细胞系SGC-7901细胞中的表达,并进一步探讨磷脂酰肌醇-3-激酶/丝苏氨酸蛋白激酶(PI3K/Akt)信号通路在RANKL诱导的胃癌细胞迁移中的作用。方法 West-ern blot检测SGC-7901细胞表面RANK蛋白的表达;RANKL刺激后磷酸化Akt(P-Akt)及Akt的表达;Transwell法测定RANKL及抑制剂刺激后细胞迁移能力的改变。结果 SGC7901细胞表达RANK蛋白。RANKL(1μg/mL)诱导SGC-7901细胞迁移能力增强,迁移增加率为57.2%±5.9%,RANKL抑制剂rOPG(5μg/mL)显著抑制RANKL诱导的细胞迁移(13.88%±3.57%,P<0.05)。RANKL刺激后30 min～3 h,SGC-7901细胞p-Akt表达升高,应用PI3K的抑制剂LY294002(50 mmol/L)显著抑制RANKL诱导的胃癌细胞SGC-7901的迁移(57.28%±5.91%vs23.18%±2.79%,P<0.05)。结论胃癌细胞系SGC-7901细胞表达受体RANK,PI3K/Akt信号通路参与RANKL诱导的SGC-7901细胞迁移。     

Early involvement of the phosphatidylinositol 3-kinase/Akt pathway in lung cancer progression

Signaling through the phosphatidylinositol 3-kinase (PI3-kinase) pathway has been associated with lung tumorigenesis. We examined the association between gene copy number of the PI3-kinase catalytic subunit alpha (PIK3CA) and phosphorylated Akt expression in invasive and preinvasive lung cancers. We sought to determine at what stage of tumor development gene copy number increase or phosphorylated Akt overexpression might affect tumor development. We assessed PIK3CA gene copy number by fluorescence in situ hybridization and expression of phosphorylated Akt by immunohistochemistry in 242 invasive and 43 preinvasive lung cancers and correlated our findings with clinical outcome. The PIK3CA was amplified in 70% of squamous carcinomas, 38% of large cell carcinomas, 19% of adenocarcinomas, and 67% of small cell lung cancers. Phosphorylated Akt overexpression was frequently observed, and strongly so in 12 to 17% of lung cancers depending on nuclear or cytoplasmic localization. Neither PIK3CA gene copy number nor phosphorylated Akt protein expression had prognostic significance. In preinvasive lesions, amplification of the PIK3CA and overexpression of phosphorylated Akt were associated with severe dysplasia and each other. These observations suggest frequent and early involvement of the PI3-kinase pathway in lung cancer.     

Inhibition of the phosphatidylinositol-3 kinase/Akt promotes G1 cell cycle arrest and apoptosis in Hodgkin lymphoma

Activation of the phosphatidylinositol 3-kinase (PI(3)K) pathway has been linked with tumour cell growth, survival and resistance to therapy in several cancer types. The active, phosphorylated form of Akt (pAkt) was found to be aberrantly expressed in Hodgkin lymphoma (HL)-derived cell lines and in Hodgkin-Reed-Sternberg (HRS) cells in 27 of 42 (64.3%) of primary lymph node sections of HL, indicative of PI(3)K activity. Akt phosphorylation was not associated with loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression, but with its phosphorylation in HL-cell lines, suggesting that its biological function is impaired. Akt phosphorylation was further induced by CD30 ligand (CD30L), CD40L and receptor activator of nuclear factor kappa B (RANK) ligand. The PI(3)K inhibitor LY294002 demonstrated antiproliferative effects in a dose- and time-dependent manner, which was associated with Akt dephosphorylation on Thr308 and Ser473 sites and dephosphorylation of the downstream ribosomal protein S6. LY209002 induced cell cycle arrest in the G0/G1 phase and apoptosis, which were associated with upregulation of MDM2, downregulation of cyclin D1, activation of caspase 9 and poly-ADP-ribose polymerase cleavage. The Akt inhibitor QLT394 also demonstrated antiproliferative effects in a dose- and time-dependent manner, dephosphorylated ribosomal S6 and cleaved caspase 9. Collectively, these data suggest that the aberrant activation of the PI(3)K/Akt survival pathway in HRS cells is not because of loss of PTEN expression. Our data suggest that PTEN phosphorylation and activation of CD30, CD40 and RANK may play a role in activating Akt in HRS cells.     

High prevalence and mutual exclusivity of genetic alterations in the phosphatidylinositol-3-kinase/akt pathway in thyroid tumors

CONTEXT: Genetic alterations in the phosphatidylinositol-3-kinase (PI3K)/Akt pathway and their role in thyroid tumor pathogenesis in Chinese people remain undefined. OBJECTIVE: The objective of the study was to examine the major genetic alterations and their relationship in the PI3K/Akt pathway in differentiated thyroid tumors in a Chinese cohort. DESIGN: We used real-time quantitative PCR for the analysis of PIK3CA copy gain and direct DNA sequencing for the detection of PIK3CA, RAS, and PTEN mutations on genomic DNA isolated from 234 thyroid tumors, including 31 follicular thyroid cancer (FTC), 141 papillary thyroid cancer (PTC), and 62 follicular thyroid adenoma (FTA). RESULTS: We found PIK3CA copy gain (defined as four or more copies) in nine of 31 FTC (29%), 20 of 141 PTC (14%), and five of 62 FTA (8%); PIK3CA gene mutations in four of 31 FTC (13%), one of 141 PTC (1%), and none of 62 FTA (0%); Ras mutations in three of 31 FTC (10%) and none of the 141 PTC and 62 FTA; and PTEN mutations in two of 31 FTC (6%) and none of 62 FTA (0%). Collectively, nine of 31 FTC (29%) vs. none of 62 FTA (0%) (P < 0.01) harbored one of the mutations, and when PIK3CA copy gain was included, 16 of 31 FTC (52%) vs. five of 62 FTA (8%) (P < 0.01) harbored any genetic alteration in the PI3K/Akt pathway. Mutual exclusivity was seen among all these PI3K/Akt pathway-related genetic alterations in all thyroid tumors except for two cases that harbored two genetic alterations. CONCLUSION: These data from a Chinese cohort provide further genetic evidence suggesting that dysregulated PI3K/Akt pathway plays a significant role in the pathogenesis of thyroid tumors, particularly FTC.     

胃癌淋巴结转移与VEGF—D、VEGFR-3、LVD的关系

目的探讨胃癌淋巴结转移与血管内皮生长因子D（VEGF—D）、血管内皮生长因子受体3（VEGFR-3）、淋巴管密度（LVD）表达间的关系。方法对59例胃癌术后标本采用免疫组织化学sP法检测VEGF—D表达,用VEGFR-3抗体免疫组织化学sP法标记淋巴管,检测肿瘤组织及正常组织LVD。结果VEGF—D、VEGFR-3在癌组织中表达率分别为59．32％、67．80％,明显高于癌旁不典型增生组织及正常胃黏膜组织（P〈0．05）。癌周组织的LVD表达为（21．29±8．21）,明显高于周边正常组织（P〈0．05）。VEGF—D表达阳性组35例与阴性组24例的LVD分别为（23．15±7．58）和（11．93±5．31）,其差异具有统计学意义（P〈0．05）。VEGF—D、LVD在癌组织中的表达与淋巴结直径、淋巴结分期、浸润深度、TNM分期及分化程度有关（P〈0．05）。结论VEGF．D在胃癌组织中高表达,并与肿瘤的淋巴管形成及淋巴结转移密切相关。     

Leptin stimulates alpha1(I) collagen expression in human hepatic stellate cells via the phosphatidylinositol 3-kinase/Akt signalling pathway.

BACKGROUND/AIMS: Leptin has been recognized as a profibrogenic hormone in the liver and is involved in collagen type I formation by activated hepatic stellate cells (HSCs) in response to fibrogenic substances, but the molecular signal mechanisms by which leptin promotes liver fibrogenesis through upregulation of collagen type I expression is not clear. We investigated whether leptin-induced collagen type I is mediated by the Janus kinase-phosphatidylinositol 3-kinase-Akt (JAKs-PI3K-Akt) pathway in a human HSC cell line, LX-2. METHODS: LX-2 cells were treated with or without various inhibitors in the presence of leptin. RESULTS: Leptin increased alpha1(I) collagen mRNA and protein. JAK1, PI3K and Akt were activated after leptin stimulation. AG490, a JAK inhibitor, blocked JAK1 phosphorylation accompanied by inhibition of PI3K and Akt activation as well as alpha1(I) collagen mRNA expression, indicating a JAK1-dependent mechanism. Wortmannin, a PI3K inhibitor, prevented PI3K and Akt activation and resulted in suppression of alpha1(I) collagen mRNA expression, suggesting a PI3K-mediated process. These changes were reproduced by overexpression of the dominant-negative p85alpha mutant. A443654.3, an Akt inhibitor, opposed Akt activation, leading to downregulation of alpha1(I) collagen mRNA. Overexpression of the dominant-negative Akt mutant led to similar alterations. CONCLUSION: Leptin has a direct action on liver fibrogenesis by stimulating alpha1(I) collagen production in activated HSC. The process appears to be mediated by the PI3K/Akt pathway through activated JAK1.     

Ischemic preconditioning blocks BAD translocation, Bcl-xL cleavage, and large channel activity in mitochondria of postischemic hippocampal neurons

Transient forebrain or global ischemia induces delayed neuronal death in vulnerable CA1 pyramidal cells with many features of apoptosis. A brief period of ischemia, i.e., ischemic preconditioning, affords robust protection of CA1 neurons against a subsequent more prolonged ischemic challenge. Here we show that preconditioning acts via PI3K/Akt signaling to block the ischemia-induced cascade involving mitochondrial translocation of Bad, assembly of Bad with Bcl-x(L), cleavage of Bcl-x(L) to form its prodeath fragment, DeltaN-Bcl-x(L), activation of large-conductance channels in the mitochondrial outer membrane, mitochondrial release of cytochrome c and Smac/DIABLO (second mitochondria-derived activator of caspases/direct IAP-binding protein with low pI), caspase activation, and neuronal death. These findings show how preconditioning acts to prevent the release of cytochrome c and Smac/DIABLO from mitochondria and to preserve the integrity of the mitochondrial membrane. The specific PI3K inhibitor LY294002 administered in vivo 1 h before or immediately after ischemia or up to 120 h later significantly reverses preconditioning-induced protection, indicating a requirement for sustained PI3K signaling in ischemic tolerance. These findings implicate PI3K/Akt signaling in maintenance of the integrity of the mitochondrial outer membrane.     

磷酸化STAT3蛋白与胃癌患者预后及临床病理特征关系的Meta分析

目的系统评价磷酸化STAT3蛋白(p-STAT3)与胃癌患者预后及临床病理特征的相关性。方法检索从建库至2019年6月在PubMed、Embase、The Cochrance Library、万方、中国知网、维普等数据库公开发表的关于胃癌中p-STAT3蛋白表达与临床意义的研究,根据纳入及排除标准筛选文献,提取相关数据,采用Revman 5.3和Stata 12.0软件进行Meta分析。结果共纳入13篇文献,共1307例胃癌患者。Meta分析结果显示:p-STAT3蛋白高表达与胃癌患者的不良预后有关(HR=2.38,95%CI:1.89~3.01,P<0.00001),其与胃癌分化程度(OR=3.08,95%CI:1.92~4.93,P<0.00001)、TNM分期(OR=2.87,95%CI:1.75~4.71,P<0.0001)、淋巴结转移(OR=2.53,95%CI:1.35~4.73,P=0.004)、远处转移(OR=0.17,95%CI:0.09~0.36,P<0.00001)、浸润深度(OR=2.74,95%CI:1.66~4.53,P<0.0001)具有相关性,而与性别(OR=0.97,95%CI:0.74~1.27,P=0.82)、年龄(OR=0.75,95%CI:0.53~1.06,P=0.10)、肿瘤大小(OR=0.76,95%CI:0.55~1.05,P=0.10)均无相关性。结论p-STAT3蛋白与胃癌患者不良预后及胃癌分化程度、TNM分期、淋巴结转移、远处转移及肿瘤浸润深度密切相关,提示其对胃癌的发展起调控作用,可能作为预测胃癌的一个分子标志物。     

PI3K、AKT、MRP在胰腺癌中的表达及其临床意义

目的 检测PI3K、AKT、MRP蛋白在胰腺癌组织中的表达,探讨它们的临床病理学意义及三者之间的相关性.方法 采用免疫组织化学法检测43例胰腺癌组织、9例CP组织和8例正常胰腺组织中PI3K、AKT、MRP蛋白的表达.结果 PI3K、AKT、MRP在胰腺癌组织中的阳性表达率分别为46.51%、55.81%和39.53%,均高于CP和正常胰腺组织中的表达(P<0.01和P<0.05).PI3K、AKT蛋白表达与胰腺癌的淋巴结转移和TNM分期相关(P<0.05).胰腺癌组织中MRP与PBK均异常表达者为32.56%,均正常表达者为46.51%,两者呈显著正相关(r=0.581,P<0.01);MRP与AKT均异常表达者为32.56%,均正常表达者为37.21%,两者呈显著正相关(r=0.432,P<0.05);PI3K与AKT均异常表达者为37.21%,均正常表达者32.56%,两者呈显著正相关(r=0.306,P<0.05).结论 胰腺癌组织PI3K、AKT和MRP蛋白表达上调,三者呈正相关.P13K和AKT的表达与淋巴结转移及TNM分期有关.     

Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic

Mutations in genes that encode components of the phosphatidyl-inositol 3-kinase (PI3-kinase) signaling pathway are common in human cancer. The recent discovery of nonrandom somatic mutations in the PIK3CA gene of many human tumors suggests an oncogenic role for the mutated enzyme. We have determined the growth-regulatory and signaling properties of the three most frequently observed PI3-kinase mutations: E542K, E545K, and H1047R. Expressed in chicken embryo fibroblasts, all three mutants induce oncogenic transformation with high efficiency. This transforming ability is correlated with elevated catalytic activity in in vitro kinase assays. The mutant-transformed cells show constitutive phosphorylation of Akt, of p70 S6 kinase, and of the 4E-binding protein 1. Phosphorylation of S6 kinase and of 4E-binding protein 1 is regulated by the target of rapamycin (TOR) kinase and affects rates of protein synthesis. The inhibitor of TOR, rapamycin, strongly interferes with cellular transformation induced by the PI3-kinase mutants, suggesting that the TOR and its downstream targets are essential components of the transformation process. The oncogenic transforming activity makes the mutated PI3-kinase proteins promising targets for small molecule inhibitors that could be developed into effective and highly specific anticancer drugs.     

蛋白激酶B和15-脂氧合酶-1在胃癌中的表达及其临床意义

目的检测蛋白激酶B（Akt）和15-脂氧合酶-1（15-lipoxygenase-1,15-LOX-1）在胃癌及癌旁正常组织中的表达,以探讨二者在胃癌形成中的临床意义。方法采用RT-PCR法检测新鲜胃癌及癌旁正常组织标本中Akt-1、Akt-2、Akt-3和15-LOX-1 mRNA的表达;Western blot印迹法检测磷酸化Akt（p-Akt）和15-LOX-1蛋白的表达。结果Akt-1、Akt-2、Akt-3 mRNA在胃癌及癌旁正常组织中的表达水平差异均无统计学意义（P〉0.05）。p-Akt蛋白在胃癌组织中的表达显著高于癌旁正常组织（P〈0.05）。15-LOX-1蛋白及mRNA在胃癌组织的表达均低于癌旁正常组织（P〈0.05）。p-Akt蛋白表达与胃癌的肿瘤大小、淋巴结转移和TNM分期呈正相关（P〈0.05）。相关性分析表明：胃癌组织中15-LOX-1蛋白表达和p-Akt水平间无明显相关性（r=-0.252,P〉0.05）。结论Akt在胃癌的发生发展中具有促进作用。15-LOX-1蛋白可能对胃癌的发生发展有一定抑制作用,但与Akt无直接关系。     

Akt1/protein Kinase Bα is Involved in Gastric Cancer Progression and Cell Proliferation

Akt (also known as protein kinase B, PKB) is involved in a variety of biological processes, for example cell development, proliferation, and angiogenesis. Clinical studies in support of the idea that increased activity of Akt could contribute directly to gastric carcinogenesis are rare, however. In this study we discovered that phospho-Akt1 was overexpressed in human gastric cancers and its levels correlated with tumor differentiation and pTNM. Akt1 activation promoted cell survival, because the phosphatidylinositol 3-kinase(PI3K) inhibitor LY294002 inhibited Akt1 phosphorylation and inhibited cell growth, especially in cells with active Akt1. Dominant negative Akt inhibited proliferation of gastric cancer cells and induced G1 cell-cycle arrest whereas constitutively active Akt increased cell proliferation. We have therefore identified Akt1 as an active kinase that contributes to gastric cancer progression and promotes proliferation of gastric cancer cells.