Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many angiogenesis inhibitors are derived from large plasma proteins. Previous studies showed that the Kringle5-like domain (termed KV) in human apolipoprotein (a) is a potential antiangiogenic factor. However, its active region and the underling molecular mechanism remain elusive. Here, we identified an 11-amino acid peptide (named KV11) as the key region for the antiangiogenic function of the KV domain of apolipoprotein (a). We demonstrate that KV11 inhibits angiogenesis in vitro by suppressing human umbilical vein endothelial cell migration and microtubule formation. KV11 inhibits angiogenesis in chicken chorioallantoic membrane assays and mouse corneal micropocket angiogenesis assays in vivo. KV11 peptide shows no effect on tumor cell growth or proliferation, but significantly inhibits tumor growth in SCID mouse xenograft tumor model (p < 0.01) by preventing tumor angiogenesis. We elucidate that KV11 peptide suppresses angiogenesis and tumor progression by targeting the c-Src/ERK signaling pathways. Together, these studies provide the first evidence that KV11 from apolipoprotein KV domain has anti-angiogenesis functions and may be an anti-tumor drug candidate.
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PMID:A novel peptide from human apolipoprotein(a) inhibits angiogenesis and tumor growth by targeting c-Src phosphorylation in VEGF-induced human umbilical endothelial cells. 1903 65

Most types of prostate cancer (PCa) are usually initially responsive to androgenic regulation and, therefore, to androgen ablation therapy. However, in several patients tumors may progress to androgen resistance and be poorly responsive to any therapy. Many factors may account for this progression to androgen independence, including increased responsiveness to estrogens and peptide growth factors. The role of estrogens in androgen independence has been suggested by the observation that both primary and metastatic PCa express the estrogen receptor (ER-beta), a recently discovered ER subtype. On the other hand, peptide growth factors, like IGF-1, IGF-2, and the insulin-like growth factor receptor (IGF-1R), may play a role in regulating growth, survival, and invasion of PCa cells. Here, we show that both androgens and estrogens markedly upregulate the IGF-1R expression in PCa cells by activating a nongenotropic pathway and sensitizing cells to the biological effects of IGF-1. This effect is specific for IGF-1R because it does not involve the highly homologous insulin receptor. IGF-1R upregulation is caused by increased mRNA transcription. However, it does not require steroid receptor binding to DNA, but involves AR and ER binding to c-Src and subsequent activation of ERK1/2 and other cytoplasmatic kinases, which eventually stimulate IGF-1R promoter activity. In conclusion, our data indicate that both androgens and estrogens contribute to IGF system deregulation in PCa and may play a role in tumor progression to androgen independence. Inhibition of the IGF-1R or the Src-ERK pathway should be considered, therefore, as an adjuvant therapy in PCa.
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PMID:Sex steroids upregulate the IGF-1R in prostate cancer cells through a nongenotropic pathway. 1925 Feb 14

The proto-oncogene c-Src (Src) encodes a nonreceptor tyrosine kinase whose expression and activity are correlated with advanced malignancy and poor prognosis in a variety of human cancers. Nine additional enzymes with homology to Src have been identified and collectively are referred to as Src family kinases (SFKs). Together, SFKs represent the largest family of nonreceptor tyrosine kinases and interact directly with receptor tyrosine kinases, G-protein-coupled receptors, steroid receptors, signal transducers and activators of transcription, and molecules involved in cell adhesion and migration. These interactions lead to a diverse array of biological functions including proliferation, cell growth, differentiation, cell shape, motility, migration, angiogenesis, and survival. Studies investigating mutational activation of Src in human cancers suggest that this may be a rare event and that wild-type Src is weakly oncogenic. Thus, the role of Src in the development and progression of human cancer remains unclear. Recently, it was suggested that increased SFK protein levels and, more importantly, SFK tyrosine kinase activity are linked to cancer progression and metastatic disease by facilitating the action of other signaling proteins. This accumulating body of evidence indicates that SFKs may represent a promising therapeutic target for the treatment of solid tumors. This review discusses the role of SFKs in solid tumors and the recent therapeutic advances aimed at targeting this family of tyrosine kinases in cancer.
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PMID:The role of Src in solid tumors. 1958 23

The upregulation of Src family kinases (SFKs) has been implicated in cancer progression, but the molecular mechanisms regulating their transforming potentials remain unclear. Here we show that the transforming ability of all SFK members is suppressed by being distributed to the cholesterol-enriched membrane microdomain. All SFKs could induce cell transformation when overexpressed in C-terminal Src kinase (Csk)-deficient fibroblasts. However, their transforming abilities varied depending on their affinity for the microdomain. c-Src and Blk, with a weak affinity for the microdomain due to a single myristate modification at the N terminus, could efficiently induce cell transformation, whereas SFKs with both myristate and palmitate modifications were preferentially distributed to the microdomain and required higher doses of protein expression to induce transformation. In contrast, disruption of the microdomain by depleting cholesterol could induce a robust transformation in Csk-deficient fibroblasts in which only a limited amount of activated SFKs was expressed. Conversely, the addition of cholesterol or recruitment of activated SFKs to the microdomain via a transmembrane adaptor, Cbp/PAG1, efficiently suppressed SFK-induced cell transformation. These findings suggest that the membrane microdomain spatially limits the transforming potential of SFKs by sequestering them away from the transforming pathways.
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PMID:Transforming potential of Src family kinases is limited by the cholesterol-enriched membrane microdomain. 1982 64

The scaffolding postsynaptic density-95/disks large/zonula occludens-1 (PDZ) domain-containing protein melanoma differentiation associated gene-9 (MDA-9)/syntenin is a tandem PDZ protein overexpressed in human melanoma, and breast and gastric cancer cells. MDA-9/syntenin affects cancer cell motility and invasion through distinct biochemical and signaling pathways, including focal adhesion kinase and p38 mitogen-activated protein kinase (MAPK), resulting in activation of the nuclear factor (NF)-kappaB pathway. MDA-9/syntenin also promotes melanoma metastasis by activating c-Src, but how c-Src regulates NF-kappaB activation is unclear. Using a human melanoma model, we document that MDA-9/syntenin-c-Src interactions are positive regulators of NF-kappaB activation. Inhibition of c-Src by PP2 treatment, by blocking c-Src or mda-9/syntenin expression with small interfering RNA, or in c-Src (-/-) knockout cell lines, reduces NF-kappaB activation following overexpression of mda-9/syntenin or c-Src. Deletion or point mutations of the PDZ binding motif preventing MDA-9/syntenin association with c-Src reveals that both PDZ domains, with PDZ2 being the dominant module, are required for activating downstream signaling pathways, including p38 MAPK and NF-kappaB. We also document that MDA-9/syntenin-c-Src complexes functionally cooperate with NF-kappaB to promote anchorage-independent growth, motility and invasion of melanoma cells. These findings underscore PDZ domains of MDA-9/syntenin as promising potential therapeutic targets for intervening in a decisive component of cancer progression, namely, metastatic tumor spread.
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PMID:Src kinase activation is mandatory for MDA-9/syntenin-mediated activation of nuclear factor-kappaB. 2022 39

Many human cancers express elevated levels of cyclooxygenase-2 (COX-2), an enzyme responsible for the biosynthesis of prostaglandins. Available clinical data establish the protective effect of COX-2 inhibition on human cancer progression. However, despite these encouraging outcomes, the appearance of unwanted side effects remains a major hurdle for the general application of COX-2 inhibitors as effective cancer drugs. Hence, a better understanding of the molecular signals downstream of COX-2 is needed for the elucidation of drug targets that may improve cancer therapy. Here, we show that the COX-2 product prostaglandin E(2) (PGE(2)) acts on cognate receptor EP4 to promote the migration of A549 lung cancer cells. Treatment with PGE(2) enhances tyrosine kinase c-Src activation, and blockade of c-Src activity represses the PGE(2)-mediated lung cancer cell migration. PGE(2) affects target cells by activating four receptors named EP1 to EP4. Use of EP subtype-selective ligand agonists suggested that EP4 mediates prostaglandin-induced A549 lung cancer cell migration, and this conclusion was confirmed using a short hairpin RNA approach to specifically knock down EP4 expression. Proximal EP4 effectors include heterotrimeric Gs and betaArrestin proteins. Knockdown of betaArrestin1 expression with shRNA significantly impaired the PGE(2)-induced c-Src activation and cell migration. Together, these results support the idea that increased expression of the COX-2 product PGE(2) in the lung tumor microenvironment may initiate a mitogenic signaling cascade composed of EP4, betaArrestin1, and c-Src which mediates cancer cell migration. Selective targeting of EP4 with a ligand antagonist may provide an efficient approach to better manage patients with advanced lung cancer.
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PMID:Prostaglandin E2 promotes lung cancer cell migration via EP4-betaArrestin1-c-Src signalsome. 2035 98

G protein-coupled receptors (GPCRs) comprise a large family of membrane receptors involved in signal transduction. These receptors are linked to a variety of physiological and biological processes such as regulation of neurotransmission, growth, cell differentiation and oncogenesis among others. Some of the effects of GPCRs are known to be mediated by the activation of MAPK pathways. Several GPCRs are also able to transactivate receptors with tyrosine kinase activity (TKR) such as EGFR and HER2 and thus to control DNA synthesis and cell proliferation. The interaction between these receptors not only plays an important physiological role but its disregulation can induce pathological states such as cancer. For this reason, the crosstalk between these two types of receptors can be considered a possible mechanism for cell transformation, tumor progression, reactivation of the metastatic disease, and the acquisition of resistance to therapies targeting TKR receptors. The transactivation of some TKRs by GPCRs is related to the lost of response of TKRs to inhibitors of TK activity, mainly by the activation of the c-Src protein which can directly phosphorylate and activate the cytoplasmic domain of a TKR. For these reason, the dual inhibition of GPCRs and TKRs in some types of cancer has been proposed as a better strategy to kill tumor cells. Increased understanding of the mechanisms that interconnect the two pathways regulated by GPCRs and TKRs may facilitate the design of new therapeutic strategies.
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PMID:Tyrosine kinase receptor transactivation associated to G protein-coupled receptors. 2045 Apr 75

Activation of Src family kinases is an important event downstream of integrin adhesion signaling in many cell types. A particularly intriguing connection between an integrin and a Src family kinase was first discovered in platelets, where the selective direct interaction of alphaIIbbeta3 integrins with c-Src promotes full kinase activation of c-Src through its local clustering by the cytoplasmic tail of the beta3 integrin subunit. The same integrin beta3-c-Src interaction not only drives platelet aggregation, but it also promotes the oncogenic potential of c-Src and drives tumor growth by alphavbeta3-expressing tumor cells, which may explain why increased activity of c-Src and elevated levels of integrin alphavbeta3 are often found in the same tumor types. Moreover, recent evidence from patient material and in vivo studies strongly indicate that this oncogenic signaling complex, consisting of c-Src and alphavbeta3, underlies tumor progression of human tumors. Here, we give an overview of the beta3-c-Src interaction and its implications for signaling in platelets and tumor cells, and we mention the possibilities for therapeutic intervention that is aimed at disrupting the beta3-c-Src interaction for antithrombotic and anticancer purposes.
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PMID:The interaction of SRC kinase with beta3 integrin tails: a potential therapeutic target in thrombosis and cancer. 2056 33

The aberrant activation of c-Src regulates multiple functions during tumor progression. This study was conducted to investigate the role of c-Src suppression in epithelial to mesenchymal transition (EMT) process in human breast carcinoma cells. c-Src suppression by PP2 (a Src-family kinase inhibitor) or small interfering RNA (siRNA) was carried out in MCF-7 and MDA-MB-231 cells. Cell migration was analyzed by wound-healing assay. The transcription and protein levels of EMT markers and transcription factors were evaluated by reverse transcription-PCR and Western blot analysis, respectively. The changed cell morphology was photographed by light microscope. c-Src suppression by PP2 or siRNA reversed the mesenchymal-like phenotype in MDA-MB-231 cells. E-cadherin was upregulated in MCF-7 and MDA-MB-231 cells after c-Src suppression, whereas vimentin was downregulated in MDA-MB-231 cells. Slug and SIP1 were downregulated after c-Src suppression in MCF-7 and MDA-MB-231 cells, whereas Twist was unchanged. These results suggest that c-Src suppression by PP2 or siRNA may inhibit EMT through regulation of different transcription factors in breast carcinoma cells that have different metastatic potential.
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PMID:Inhibition of epithelial to mesenchymal transition in metastatic breast carcinoma cells by c-Src suppression. 2070 89

The nonreceptor tyrosine kinase c-Src is frequently over-expressed or hyperactivated in various human cancers and contributes to cancer progression in cooperation with up-regulated growth factor receptors. However, Src-selective anticancer drugs are still in clinical trials. To identify more effective inhibitors of c-Src-mediated cancer progression, we developed a new screening platform using Csk-deficient cells that can be transformed by c-Src. We found that purvalanol A, developed as a CDK inhibitor, potently suppressed the anchorage-independent growth of c-Src-transformed cells, indicating that the activation of CDKs contributes to the c-Src transformation. We also found that purvalanol A suppressed the c-Src activity as effectively as the Src-selective inhibitor PP2, and that it reverted the transformed morphology to a nearly normal shape with less cytotoxicity than PP2. Purvalanol A induced a strong G2-M arrest, whereas PP2 weakly acted on the G1-S transition. Furthermore, when compared with PP2, purvalanol A more effectively suppressed the growth of human colon cancer HT29 and SW480 cells, in which Src family kinases and CDKs are activated. These findings demonstrate that the coordinated inhibition of cell cycle progression and tyrosine kinase signaling by the multi-selective purvalanol A is effective in suppressing cancer progression associated with c-Src up-regulation.
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PMID:Purvalanol A, a CDK inhibitor, effectively suppresses Src-mediated transformation by inhibiting both CDKs and c-Src. 2082 94


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