Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene amplification is common in solid tumors and is associated with adverse prognosis, disease progression, and development of drug resistance. A small segment from chromosome 17q11-12 containing the HER-2/Neu gene is amplified in about 25% of breast cancer. HER-2/Neu amplification is associated with adverse prognosis and may predict response to chemotherapy and hormonal manipulation. Moreover, HER-2/Neu amplification may select patients for anti-HER-2/Neu-based therapy with Herceptin. We and others recently described a common sequence element from the HER-2/Neu region that was amplified in breast cancer cells. In addition, most, if not all, of the amplified genes from this region display overexpression. This raises the intriguing possibility that genes immediately adjacent to HER-2/Neu may influence the biological behavior of breast cancer carrying HER-2/Neu amplification and serve as rational targets for therapy. By extracting sequence information from public databases, we have constructed a contig in bacterial artificial chromosomes (BACs) that extends from HER-2/Neu to a phosphotidylinositol phosphate kinase (PIPK), Pip4k2beta from 17q11-12. Although a role of PI-3-kinase and AKT in cancer biology has been previously described, PIPK has not been previously implicated. We show that Pip4k2beta, initially known as Pip5k2beta, is amplified in a subset of breast cancer cell lines and primary breast cancer samples that carry HER-2/Neu amplification. Out of eight breast cancer cell lines with HER-2/Neu amplification, three have concomitant amplification of the Pip4k2beta gene--UACC-812, BT-474 and ZR-75-30. Similarly, two out of four primary breast tumors with HER-2/Neu amplification carry Pip4k2beta gene amplification. Intriguingly, one tumor displays an increase in the gene copy number of Pip4k2beta that is significantly more than that of HER-2/Neu. Moreover, dual color FISH reveals that amplified Pip4k2beta gene may exist in a distinct structure from that of HER-2/Neu in ZR-75-30 cell line. These studies suggest that Pip4k2beta may reside on an amplification maximum distinct from that of HER-2/Neu and serve as an independent target for amplification and selective retention. Pip4k2beta amplification is associated with overexpression at the RNA and protein level in breast cancer cell lines. Stable expression of Pip4k2beta in breast cancer cell lines with and without HER-2/Neu amplification increases cell proliferation and anchorage-independent growth. The above observations implicate Pip4k2beta in the development and/or progression of breast cancer. Our study suggests that Pip4k2beta may be a distinct target for gene amplification and selective retention from 17q11-12.
 ...
PMID:Overexpression of the amplified Pip4k2beta gene from 17q11-12 in breast cancer cells confers proliferation advantage. 1469 57

The expression of the NH2 terminally truncated ErbB2 receptor (p95ErbB2) in breast cancer correlates with metastatic disease progression compared with the expression of full-length p185ErbB2. We now show that heregulin (HRG), but not EGF, stimulates p95ErbB2 phosphorylation in BT474 breast cancer cells. Furthermore, phospho-p95ErbB2 forms heterodimers with ErbB3, but not EGFR, while p185ErbB2 heterodimerizes with both EGFR and ErbB3. The predilection of p95ErbB2 to heterodimerize with ErbB3 provides an explanation for its regulation by HRG, an ErbB3 ligand. GW572016, a reversible small molecule inhibitor of EGFR and ErbB2 tyrosine kinases, inhibits baseline p95ErbB2 phosphorylation in BT474 cells and tumor xenografts. Inhibition of p95ErbB2, p185ErbB2, and EGFR phosphorylation by GW572016 resulted in the inhibition of downstream phospho-Erk1/2, phospho-AKT, and cyclin D steady-state protein levels. Increased phosphorylation of p95ErbB2 and AKT in response to HRG was abrogated to varying degrees by GW572016. In contrast, trastuzumab did not inhibit p95ErbB2 phosphorylation or the expression of downstream phospho-Erk1/2, phospho-AKT, or cyclin D. It is tempting to speculate that trastuzumab resistance may be mediated in part by the selection of p95ErbB2-expressing breast cancer cells capable of exerting potent growth and prosurvival signals through p95ErbB2-ErbB3 heterodimers. Thus, p95ErbB2 represents a target for therapeutic intervention, and one that is sensitive to GW572016 therapy.
 ...
PMID:Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. 1473

Geranylgeranyltransferase I inhibitors (GGTIs) represent a new class of anticancer drugs. However, the mechanism by which GGTIs inhibit tumor cell growth is still unclear. Here, we demonstrate that GGTI-298 and GGTI-2166 induce apoptosis in both cisplatin-sensitive and -resistant human ovarian epithelial cancer cells by inhibition of PI3K/AKT and survivin pathways. Following GGTI-298 or GGTI-2166 treatment, kinase levels of PI3K and AKT were decreased and survivin expression was significantly reduced. Ectopic expression of constitutively active AKT2 and/or survivin significantly rescue human cancer cells from GGTI-298-induced apoptosis. Previous studies have shown that Akt mediates growth factor-induced survivin, whereas p53 inhibits survivin expression. However, constitutively active AKT2 failed to rescue the GGTIs downregulation of survivin. Further, GGTIs suppress survivin expression and induce programmed cell death in both wild-type p53 and p53-deficient ovarian cancer cell lines. These data indicate that GGTI-298 and GGTI-2166 induce apoptosis by targeting PI3K/AKT and survivin parallel pathways independent of p53. Owing to the fact that upregulation of Akt and survivin as well as inactivation of p53 are frequently associated with chemoresistance, GGTIs could be valuable agents to overcome antitumor drug resistance.
 ...
PMID:Phosphatidylinositol-3-OH kinase/AKT and survivin pathways as critical targets for geranylgeranyltransferase I inhibitor-induced apoptosis. 1473 5

PTEN is a tumor suppressor gene that is frequently mutated in human tumors. It functions primarily as a lipid phosphatase and plays a key role in the regulation of phosphatidylinositol-3'-kinase. PTEN appears to play a crucial role in modulating apoptosis by reducing the levels of PtdIns(3,4,5)P3, a phospholipid that activates AKT, a central regulator of apoptosis. To understand the role of PTEN in regulating cell proliferation and apoptosis, we stably overexpressed PTEN in PC3 cells, which are prostate cancer cells that lack PTEN. Overexpression of PTEN in two different clones inhibited cell proliferation and increased serum starvation-induced apoptosis, as compared to control cells. Interestingly, PTEN overexpression resulted in a 44-60% reduction in total insulin-like growth factor-I receptor (IGF-IR) protein levels and a 49-64% reduction in cell surface IGF-IR expression. [35S]methionine pulse experiments in PC3 cells overexpressing PTEN demonstrated that these cells synthesize significantly lower levels of the IGF-IR precursor, whereas PTEN overexpression had no effect on IGF-IR degradation. Taken together, our results show that PTEN can regulate cell proliferation and apoptosis through inhibition of IGF-IR synthesis. These results have important implications for understanding the roles of PTEN and the IGF-IR in prostate cancer cell tumorigenesis.
 ...
PMID:PTEN inhibits cell proliferation and induces apoptosis by downregulating cell surface IGF-IR expression in prostate cancer cells. 1473 13

Crk-associated substrate (Cas) is highly phosphorylated by v-Src and plays a critical role in v-Src-induced cell transformation. In this study, we found that the Src homology (SH) 3 domain of Cas blocked v-Src-stimulated anchorage-independent cell growth, Matrigel invasion, and tumor growth in nude mice. Biochemical analysis revealed that the Cas SH3 domain selectively inhibited v-Src-stimulated activations of AKT and JNK, but not ERK and STAT3. Attenuation of the AKT pathway by the Cas SH3 domain rendered v-Src-transformed cells susceptible to apoptosis. Inhibition of the JNK pathway by the Cas SH3 domain led to suppression of v-Src-stimulated invasion. Taken together, our results indicate that the Cas SH3 domain has an anti-tumor function, which severely impairs the transforming potential of v-Src.
 ...
PMID:Blockade of v-Src-stimulated tumor formation by the Src homology 3 domain of Crk-associated substrate (Cas). 1474 71

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a natural product of Capsicum species, is known to induce excitation of nociceptive terminals involved in pain perception. Recent studies have also shown that capsaicin not only has chemopreventive properties against certain carcinogens and mutagens but also exerts anticancer activity. Here, we demonstrated the antiangiogenic activity of capsaicin using in vitro and in vivo assay systems. In vitro, capsaicin inhibited vascular endothelial growth factor (VEGF) -induced proliferation, DNA synthesis, chemotactic motility, and capillary-like tube formation of primary cultured human endothelial cells. Capsaicin inhibited both VEGF-induced vessel sprouting in rat aortic ring assay and VEGF-induced vessel formation in the mouse Matrigel plug assay. Moreover, capsaicin was able to suppress tumor-induced angiogenesis in chick chorioallantoic membrane assay. Capsaicin caused G(1) arrest in endothelial cells. This effect correlated with the down-regulation of the expression of cyclin D1 that led to inhibition of cyclin-dependent kinase 4-mediated phosphorylation of retinoblastoma protein. Signaling experiments show that capsaicin inhibits VEGF-induced p38 mitogen-activated protein kinase, p125(FAK), and AKT activation, but its molecular target is distinct from the VEGF receptor KDR/Flk-1. Taken together, these results demonstrate that capsaicin is a novel inhibitor of angiogenesis and suggest that it may be valuable to develop pharmaceutical drugs for treatment of angiogenesis-dependent human diseases such as tumors.
 ...
PMID:Capsaicin inhibits in vitro and in vivo angiogenesis. 1474 80

EKB-569 is an irreversible inhibitor of epidermal growth factor receptor (EGF-R) tyrosine kinase. It inhibits EGF-induced phosphorylation of EGF-R and the growth of tumors that overexpress EGF-R in animal models. In clinical trials, EKB-569 and all other EGF-R inhibitors cause skin rashes. To understand the latter phenomenon, the effect of EKB-569 on EGF-R as well as downstream signaling to phosphoinositide 3-kinase-protein kinase B (AKT), extracellular signal-regulated kinase 1 and 2 (ERK1/2), or signal transducer and activator of transcription 3 (STAT3) pathways were compared in tumor cell lines and normal human keratinocytes (NHEK) grown in tissue culture. Tumor cell lines that have high (A431 epidermoid and MDA-468 breast carcinomas) and low (MCF-7 breast carcinoma) expression of EGF-R were used. NHEK cells express at least 15-fold less EGF-R than A431 cells. EKB-569 was a potent inhibitor of proliferation in NHEK, A431, and MDA-468 cells (IC(50) = 61, 125, and 260 nM, respectively) but not MCF-7 cells (IC(50) = 3600 nM). EKB-569 was also a potent inhibitor of EGF-induced phosphorylated EGF-R (pEGF-R) in A431 and NHEK cells (IC(50) = 20-80 nM). The reduction in pEGF-R paralleled inhibition of phosphotyrosine-705 STAT3, while the inhibition of phosphorylated AKT and phosphorylated ERK1/2 occurred at higher concentrations of EKB-569 (75-500 nM) in both A431 and NHEK cells. The effects were specific because EKB-569 did not inhibit the nuclear factor-kappaB pathway. It is proposed that skin toxicity associated with EKB-569 is due to inhibition of EGF-R signaling. Downstream signal transduction markers, particularly the activation status of STAT3, may be useful surrogate markers to guide clinical development of EGF-R inhibitors.
 ...
PMID:Phosphorylation of extracellular signal-regulated kinase 1 and 2, protein kinase B, and signal transducer and activator of transcription 3 are differently inhibited by an epidermal growth factor receptor inhibitor, EKB-569, in tumor cells and normal human keratinocytes. 1474 72

Resveratrol (RES), a natural phytoalexin, has antiproliferative activity in human-derived cancer cells and in rodent models of tumor development. We have previously shown that RES induced apoptotic death in estrogen-responsive MCF-7 human breast cancer cells. Recent data have indicated that the estrogen receptor-alpha (ERalpha), through interaction with p85, regulates phosphoinositide 3-kinase (PI3K) activity, revealing a physiologic, nonnuclear function of the ERalpha potentially relevant in cell proliferation and apoptosis. In our study, using MCF-7, we have analyzed the ability of RES to modulate the ERalpha-dependent PI3K pathway. Immunoprecipitation and kinase activity assays showed that RES increased the ERalpha-associated PI3K activity with a maximum stimulatory effect at concentrations close to 10 microM; concentrations >50 microM decreased PI3K activity. Stimulation of PI3K activity by RES was ERalpha-dependent since it could be blocked by the antiestrogen ICI 182,780. RES did not affect p85 protein expression but induced the proteasome-dependent degradation of the ERalpha. Nevertheless, the amount of PI3K immunoprecipitated by the ERalpha remained unchanged in presence of RES, indicating that ERalpha availability was not limiting PI3K activity. Phosphoprotein kinase B (pPKB/AKT) followed the pattern of PI3K activity, whereas RES did not affect total PKB/AKT expression. PKB/AKT downstream target glycogen synthase kinase 3 (GSK3) also showed a phosphorylation pattern that followed PI3K activity. We propose a mechanism through which RES could inhibit survival and proliferation of estrogen-responsive cells by interfering with an ERalpha-associated PI3K pathway, following a process that could be independent of the nuclear functions of the ERalpha.
 ...
PMID:Resveratrol modulates the phosphoinositide 3-kinase pathway through an estrogen receptor alpha-dependent mechanism: relevance in cell proliferation. 1475 Jan 65

The phosphatidilinositol 3-kinase/protein kinase B (PI3K-AKT) pathway presents an exciting new target for molecular therapeutics. While exhibiting great promise, additional preclinical and clinical studies will be required to determine how best to target this pathway to improve patient outcome. A number of questions need to be answered prior to the implementation into patient care practices. As described below, the PI3K-AKT pathway regulates a broad spectrum of cellular processes, some of which are necessary to maintain normal physiological functions, which potentially contribute to the toxicity of the drugs targeting the pathway. Elucidation of the precise function of the PI3K-AKT isoforms, could promote the development of isoform specific approaches to provide a selective action on tumor cells. However, whether this will be possible due to conservation of structural domains is not yet clear. Inhibition of the PI3K-AKT pathway at multiple sites or a combination with inhibitors of different signaling pathways may allow the development of an acceptable therapeutic index for cancer management. Further, inhibition of the PI3K-AKT pathway combined with conventional chemotherapy or radiation therapy may provide a more effective strategy to improve patient outcome. As molecular therapeutics target the underlying defects in patient tumors, molecular diagnostics are required to identify patients with particular genetic aberrations in the pathway. It will be critical to provide adequate therapeutic strategies tailored to each patient. In addition, patients with different genetic backgrounds or in different health conditions could respond adversely to particular therapeutics. Therefore, identification of patients for particular drugs based on the underlying genetic defects in the tumor as well as the characteristics of the host would be of benefit for improving patient outcome. Linking the targeted therapeutics to molecular imaging approaches will determine appropriate biologically relevant dose for patients. It will also define expected tumor responsiveness and eventually will improve efficacy and decrease toxicity. In this regard, personalized molecular medicine is likely to soon provide effective cancer treatment.
 ...
PMID:Targeting PI3K-AKT pathway for cancer therapy. 1476 63

Maintenance of cellular homeostasis is integral to appropriate regulation of cellular signaling and cell growth and division. In this study, we report the development and quality assessment of a pathway-focused microarray comprising genes involved in cellular homeostasis. Since nicotine is known to have highly modulatory effects on the intracellular calcium homeostasis, we therefore tested the applicability of the homeostatic pathway-focused microarray on the gene expression in PC-12 cells treated with 1 mM nicotine for 48 h relative to the untreated control cells. We first provided a detailed description of the focused array with respect to its gene and pathway content and then assessed the array quality using a robust regression procedure that allows for the exclusion of unreliable measurements while decreasing the number of false positives. As a result, the mean correlation coefficient between duplicate measurements of the arrays used in this study (control vs. nicotine treatment, three samples each) has increased from 0.974+/-0.017 to 0.995+/-0.002. Furthermore, we found that nicotine affected various structural and signaling components of the AKT/PKB signaling pathway and protein synthesis and degradation processes in PC-12 cells. Since modulation of intracellular calcium concentrations ([Ca(2+)](i)) and phosphatidylinositol signaling are important in various biological processes such as neurotransmitter release and tissue pathogenesis including tumor formation, we expect that the homeostatic pathway-focused microarray potentially can be used for the identification of unique gene expression profiles in comparative studies of drugs of abuse and diverse environmental stimuli, such as starvation and oxidative stress.
 ...
PMID:Application of a customized pathway-focused microarray for gene expression profiling of cellular homeostasis upon exposure to nicotine in PC12 cells. 1496 41


<< Previous 1 2 3 4 5 6 7 8 9 10