Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the RAS family of small G-proteins is essential for follicle stimulating hormone-induced signaling events and the regulation of target genes in cultured granulosa cells. To analyze the functions of RAS protein in granulosa cells during ovarian follicular development in vivo, we generated conditional knock-in mouse models in which the granulosa cells express a constitutively active KrasG12D. The KrasG12D mutant mice were subfertile and exhibited signs of premature ovarian failure. The mutant ovaries contained numerous abnormal follicle-like structures that were devoid of mitotic and apoptotic cells and cells expressing granulosa cell-specific marker genes. Follicles that proceeded to the antral stage failed to ovulate and expressed reduced levels of ovulation-related genes. The human chorionic gonadotropin-stimulated phosphorylation of ERK1/2 was markedly reduced in mutant cells. Reduced ERK1/2 phosphorylation was due, in part, to increased expression of MKP3, an ERK1/2-specific phosphatase. By contrast, elevated levels of phospho-AKT were evident in granulosa cells of immature KrasG12D mice, even in the absence of hormone treatments, and were associated with the progressive decline of FOXO1 in the abnormal follicle-like structures. Thus, inappropriate activation of KRAS in granulosa cells blocks the granulosa cell differentiation pathway, leading to the persistence of abnormal non-mitotic, non-apoptotic cells rather than tumorigenic cells. Moreover, those follicles that reach the antral stage exhibit impaired responses to hormones, leading to ovulation failure. Transient but not sustained activation of RAS in granulosa cells is therefore crucial for directing normal follicle development and initiating the ovulation process.
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PMID:Selective expression of KrasG12D in granulosa cells of the mouse ovary causes defects in follicle development and ovulation. 1850 27

Somatic PIK3CA mutations are often present in colorectal cancer. Mutant PIK3CA activates AKT signaling, which up-regulates fatty acid synthase (FASN). Microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) are important molecular classifiers in colorectal cancer. However, the relationship between PIK3CA mutation, MSI and CIMP remains uncertain. Using Pyrosequencing technology, we detected PIK3CA mutations in 91 (15%) of 590 population-based colorectal cancers. To determine CIMP status, we quantified DNA methylation in eight CIMP-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by real-time polymerase chain reaction (MethyLight). PIK3CA mutation was significantly associated with mucinous tumors [P = .0002; odds ratio (OR) = 2.44], KRAS mutation (P < .0001; OR = 2.68), CIMP-high (P = .03; OR = 2.08), phospho-ribosomal protein S6 expression (P = .002; OR = 2.19), and FASN expression (P = .02; OR = 1.85) and inversely with p53 expression (P = .01; OR = 0.54) and beta-catenin (CTNNB1) alteration (P = .004; OR = 0.43). In addition, PIK3CA G-to-A mutations were associated with MGMT loss (P = .001; OR = 3.24) but not with MGMT promoter methylation. In conclusion, PIK3CA mutation is significantly associated with other key molecular events in colorectal cancer, and MGMT loss likely contributes to the development of PIK3CA G>A mutation. In addition, Pyrosequencing is useful in detecting PIK3CA mutation in archival paraffin tumor tissue. PIK3CA mutational data further emphasize heterogeneity of colorectal cancer at the molecular level.
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PMID:PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations. 1851 90

KRAS activation and PTEN inactivation are frequent events in endometrial tumorigenesis, occurring in 10% to 30% and 26% to 80% of endometrial cancers, respectively. Because we have recently shown activating mutations in fibroblast growth factor receptor 2 (FGFR2) in 16% of endometrioid endometrial cancers, we sought to determine the genetic context in which FGFR2 mutations occur. Analysis of 116 primary endometrioid endometrial cancers revealed that FGFR2 and KRAS mutations were mutually exclusive, whereas FGFR2 mutations were seen concomitantly with PTEN mutations. Here, we show that shRNA knockdown of FGFR2 or treatment with a pan-FGFR inhibitor, PD173074, resulted in cell cycle arrest and induction of cell death in endometrial cancer cells with activating mutations in FGFR2. This cell death in response to FGFR2 inhibition occurred within the context of loss-of-function mutations in PTEN and constitutive AKT phosphorylation, and was associated with a marked reduction in extracellular signal-regulated kinase 1/2 activation. Together, these data suggest that inhibition of FGFR2 may be a viable therapeutic option in endometrial tumors possessing activating mutations in FGFR2, despite the frequent abrogation of PTEN in this cancer type.
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PMID:Inhibition of activated fibroblast growth factor receptor 2 in endometrial cancer cells induces cell death despite PTEN abrogation. 1875 3

Overexpression of epidermal growth factor receptor (EGFR) and mutation of pten tumor suppressor gene in human cancer cells leads to activated EGFR downstream signaling including PI3-kinase/AKT (PI3K/AKT) and/or mitogen-activated protein kinases (RAS/RAF/MAPK) and have been linked to resistance to anti-EGFR targeted therapies. Cetuximab is a chimeric IgG1 monoclonal antibody that binds the EGFR with high specificity and have been developed as promising therapeutic anticancer treatments in several solid tumors, including colorectal and head and neck squamous cell carcinomas. Cetuximab activity is related to PI3K/AKT and RAS/RAF/MAPK signaling pathways functionality and its activity has been shown to be higher in wild-type KRAS tumors. To study the influence of PTEN expression on cell response to cetuximab, we used wild-type KRAS, PTEN-null, EGFR overexpressing PC3 prostate cancer cells. Reintroduction of PTEN significantly reduced the constitutive overexpression of phosphorylated-AKT (p-AKT) and downstream kinases (p-GSK3beta and p-P70S6 kinase) as well as phosphorylated-ERK1/2 (p-ERK1/2) and consequently significantly restored cetuximab-induced cell growth inhibition and apoptosis induction. Taken together, the results achieved in the present study show that PTEN controls the cellular response to cetuximab in KRAS wild-type prostate carcinoma PC3 cells through the regulation of AKT phosphorylation and restoration of the functionality of EGFR downstream signaling. Extrapolation of these findings to clinical situation, suggests that the assessment of EGFR downstream signaling functionality could be proposed as a diagnostic response predictive marker for anti-EGFR targeted therapies.
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PMID:PTEN expression controls cellular response to cetuximab by mediating PI3K/AKT and RAS/RAF/MAPK downstream signaling in KRAS wild-type, hormone refractory prostate cancer cells. 1921 33

Despite rapid advances in understanding ovarian cancer etiology, epithelial ovarian cancer remains the most lethal form of gynecologic cancers in the United States. The four morphologically-defined epithelial ovarian cancer subtypes-serous, endometrioid, mucinous, and clear cell carcinomas--are generally believed to originate from ovarian epithelial cells. Although it remains unclear how this single cell layer gives rise to morphologically distinct cancers, it has been suggested that early genetic events may direct the differentiation of ovarian epithelial cells. A number of genetic alterations are frequently encountered during ovarian tumorigenesis, including oncogenic activities of KRAS, BRAF and AKT, and silencing mutations of TP53, RB and PTEN. However, knowledge about how these genetic elements are coordinated during ovarian cancer initiation and progression is very limited. The establishment of cell-culture systems and rodent-based models has made big strides towards a better understanding of the genetic bases of human epithelial ovarian tumorigenesis. More importantly, the rise of genetically-engineered rodent and human models, particularly in the past five years, has provided key insight in the role of specific genes during ovarian tumorigenesis. In this review, we offer a comprehensive coverage of currently-available in vitro and in vivo models of human epithelial ovarian cancer, focusing on latest updates of genetically-modified rodent and human models and the valuable information conveyed by them.
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PMID:Epithelial ovarian cancer: focus on genetics and animal models. 1922 85

Ovarian clear cell carcinoma (CCC) is one of the most malignant types of ovarian carcinomas, particularly at advanced stages. Unlike the more common type of ovarian cancer, high-grade serous carcinoma, ovarian CCC is often resistant to platinum-based chemotherapy, and therefore an effective treatment for this tumor type at advanced stages is urgently needed. In this study, we analyzed 97 ovarian CCCs for sequence mutations in KRAS, BRAF, PIK3CA, TP53, PTEN, and CTNNB1 as these mutations frequently occur in other major types of ovarian carcinomas. The samples included 18 CCCs for which affinity-purified tumor cells from fresh specimens were available, 69 microdissected tumors from paraffin tissues, and 10 tumor cell lines. Sequence mutations of PIK3CA, TP53, KRAS, PTEN, CTNNB1, and BRAF occurred in 33%, 15%, 7%, 5%, 3%, and 1% of CCC cases, respectively. Sequence analysis of PIK3CA in 28 affinity-purified CCCs and CCC cell lines showed a mutation frequency of 46%. Samples with PIK3CA mutations showed intense phosphorylated AKT immunoreactivity. These findings demonstrate that ovarian CCCs have a high frequency of activating PIK3CA mutations. We therefore suggest that the use of PIK3CA-targeting drugs may offer a more effective therapeutic approach compared with current chemotherapeutic agents for patients with advanced-stage and recurrent CCC.
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PMID:Frequent activating mutations of PIK3CA in ovarian clear cell carcinoma. 1934 52

The RAS pathway is one of the most frequently deregulated pathways in cancer. RAS signals through multiple effector pathways, including the RAF/mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK MAPK and phosphatidylinositol 3-kinase (PI3K)-AKT signaling cascades. The oncogenic potential of these effector pathways is illustrated by the frequent occurrence of activating mutations in BRAF and PIK3CA as well as loss-of-function mutations in the tumor suppressor PTEN, a negative regulator of PI3K. Previous studies have found that whereas BRAF mutant cancers are highly sensitive to MEK inhibition, RAS mutant cancers exhibit a more variable response. The molecular mechanisms responsible for this heterogeneous response remain unclear. In this study, we show that PI3K pathway activation strongly influences the sensitivity of RAS mutant cells to MEK inhibitors. Activating mutations in PIK3CA reduce the sensitivity to MEK inhibition, whereas PTEN mutations seem to cause complete resistance. We further show that down-regulation of PIK3CA resensitizes cells with co-occurring KRAS and PIK3CA mutations to MEK inhibition. At the molecular level, the dual inhibition of both pathways seems to be required for complete inhibition of the downstream mammalian target of rapamycin effector pathway and results in the induction of cell death. Finally, we show that whereas inactivation of either the MEK or PI3K pathway leads to partial tumor growth inhibition, targeted inhibition of both pathways is required to achieve tumor stasis. Our study provides molecular insights that help explain the heterogeneous response of KRAS mutant cancers to MEK pathway inhibition and presents a strong rationale for the clinical testing of combination MEK and PI3K targeted therapies.
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PMID:PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. 1940 49

Energy balance and the AKT pathway are important in colorectal cancer development and regulate p27 (cyclin-dependent kinase inhibitor-1B/CDKN1B/KIP1), which plays a role in preventing cell cycle progression. However, little is known on the clinical outcome or prognostic significance of p27 alterations in relation to patient body mass index (BMI). Among 630 colon cancers (stage I-IV) in two prospective cohort studies, we detected p27 alterations (cytoplasmic p27 localization or p27 loss) in 500 tumors (79%) by immunohistochemistry. The remaining 130 (21%) tumors were "p27-nuclear+." Cox proportional hazard models computed hazard ratios (HR) of deaths, adjusted for patient and tumoral characteristics, including p53, p21, cyclin D1, KRAS, BRAF, PIK3CA, cyclooxygenase-2, fatty acid synthase (FASN), beta-catenin, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and long interspersed nucleotide element-1 (LINE-1) hypomethylation. Compared with p27-nuclear+ patients, p27-altered patients experienced low colon cancer-specific [adjusted HR, 0.63; 95% confidence interval (95% CI), 0.42-0.94] and overall mortality (adjusted HR, 0.70; 95% CI, 0.51-0.95), independent of FASN, MSI, CIMP, LINE-1 methylation, and other potential confounders. The effect of p27 alteration on overall mortality significantly differed by BMI (P(interaction) = 0.013); adjusted HR (p27-altered versus p27-nuclear+ tumors) was 0.28 (95% CI, 0.13-0.59) for BMI >or=30 kg/m(2), 0.67 (95% CI, 0.40-1.14) for BMI 25 to 29 kg/m(2), and 0.91 (95% CI, 0.57-1.46) for BMI <25 kg/m(2). Obesity was associated with inferior overall survival among p27-nuclear+ cases (adjusted HR, 3.07; 95% CI, 1.49-6.32; versus nonobese cases), but not among p27-altered cases (adjusted HR, 1.08). In conclusion, p27 alterations in colon cancer are associated with superior prognosis. Adverse prognostic effect of obesity seems limited to patients with nuclear p27 expression, suggesting a host-tumor interaction.
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PMID:A cohort study of p27 localization in colon cancer, body mass index, and patient survival. 1950 18

The anti-epidermal growth factor receptor monoclonal antibodies cetuximab and panitumumab have established efficacy as single agent and in combination with chemotherapy in advanced colorectal cancer. However, only a small percentage of unselected patients (around 10%) are responsive to these costly agents. Mutations in the KRAS gene are associated with resistance to both cetuximab and panitumumab and account for approximately 30% to 40% of resistant patients. Nevertheless, having an intact KRAS is necessary but not sufficient to derive benefit from EGFR inhibition. Further, positive predictive markers that are currently being evaluated include an increase in EGFR gene copy number and additional data suggest that other EGFR downstream pathways such as the PI3K/PTEN/AKT/mTOR and JAK/STAT pathways are also important when considering mechanisms of EGFR antibody resistance. New data seem to support the role of BRAF mutational status. In addition, high mRNA levels of the EGFR-ligands Epiregulin and Amphiregulin have been associated with increased responsiveness to cetuximab. In this article we will review the available clinical and experimental data potentially useful for a better patients' selection.
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PMID:Anti-EGFR therapy in colorectal cancer: how to choose the right patient. 1966 67

Pharmacologic blockade of EGFR or the closely related receptor ERBB2 has modest efficacy against colorectal cancers in the clinic. Although the upregulation of ERBB3, a pseudo-kinase member of the EGFR/ERBB family, is known to contribute to EGFR inhibitor resistance in other cancers, its functions in normal and malignant intestinal epithelium have not been defined. We have shown here that the intestinal epithelium of mice with intestine-specific genetic ablation of Erbb3 exhibits no cytological abnormalities but does exhibit loss of expression of ERBB4 and sensitivity to intestinal damage. By contrast, intestine-specific Erbb3 ablation resulted in almost complete absence of intestinal tumors in the ApcMin mouse model of colon cancer. Unlike nontransformed epithelium lacking ERBB3, intestinal tumors lacking ERBB3 had reduced PI3K/AKT signaling, which led to attenuation of tumorigenesis via a tumor-specific increase in caspase-3-mediated apoptosis. Consistent with the mouse data, which suggest that ERBB3-ERBB4 heterodimers contribute to colon cancer survival, experimentally induced loss of ERBB3 in a KRAS mutant human colon cancer cell line was associated with loss of ERBB4 expression, and siRNA knockdown of either ERBB3 or ERBB4 resulted in elevated levels of apoptosis. These results indicate that the ERBB3 pseudo-kinase has essential roles in supporting intestinal tumorigenesis and suggest that ERBB3 may be a promising target for the treatment of colorectal cancers.
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PMID:Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium. 1969 Mar 88


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