Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic cancer is a lethal disease accounting for the fourth leading cause of cancer death in USA. Focal adhesion kinase (FAK) and the insulin-like growth factor-I receptor (IGF-1R) are tyrosine kinases that activate common pathways, leading to increased proliferation and cell survival. Sparse information is available regarding their contribution to the malignant behavior of pancreatic cancer. We analyzed the relationship between FAK and IGF-1R in human pancreatic cancer cells, determined which downstream signaling pathways are altered following kinase inhibition or downregulation and studied whether dual kinase inhibition represents a potential novel treatment strategy in this deadly disease. Using immunoprecipitation and confocal microscopy, we show for the first time that FAK and IGF-1R physically interact in pancreatic cancer cells and that inhibition of tyrosine phosphorylation of either kinase disrupts their interaction. Decreasing phosphorylation of either FAK or IGF-1R alone resulted in little inhibition of cell viability or increased apoptosis. However, dual inhibition of FAK, using either a dominant-negative construct (FAK-CD) or small interfering RNA, and IGF-1R, using a specific small molecule tyrosine kinase inhibitor (AEW-541) or stable expression of a truncated, mutated IGF-1R, led to a synergistic decrease in cell proliferation and phosphorylation of extracellular signal-regulated kinase (ERK) and increase in cell detachment and apoptosis compared with inhibition of either pathway alone. Dual kinase inhibition with FAK-CD and AEW-541 resulted in a marked increase in apoptosis when FAK was displaced from the focal adhesions. Inhibition of both tyrosine kinase activities via a novel single small molecular inhibitor (TAE 226), at low doses specific for FAK and IGF-1R, resulted in significant inhibition of cell viability, decrease in phosphorylation of ERK and Akt and increase in apoptosis accompanied by cleavage of Poly (ADP-ribose) polymerase (PARP) and activation of caspase-3 in pancreatic cancer cells. Thus, simultaneous inhibition of both tyrosine kinases represents a potential novel therapeutic approach in human pancreatic adenocarcinoma.
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PMID:FAK and IGF-IR interact to provide survival signals in human pancreatic adenocarcinoma cells. 1826 93

Brucea javanica fruit is thought to have anticancer properties in Chinese medicine and its extract has been shown to possess antiproliferative and pro-apoptotic activities on human carcinoma cells. In the present study we demonstrated for the first time that Fructus Bruceae extract exhibited cytotoxic effects on the three pancreatic adenocarcinoma cell lines, PANC-1, SW1990 and CAPAN-1; the effects were comparable to those exhibited by camptothecin in our culture system. In addition, Fructus Bruceae extract induced fragmentation of genomic DNA, as evidenced by Hoechst staining and the cell death detection ELISA(PLUS) assay. Western blot analysis further showed down-regulation of pro-caspase 3 protein expression, indicating that the observed cytotoxic effects of the extract were associated with induction of apoptosis. These findings are not only significant in the development of traditional Chinese medicine as an alternative treatment for pancreatic cancer, but also in the elucidation of the potential mechanism(s) of Fructus Bruceae extract in cancer therapy.
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PMID:Brucea javanica fruit induces cytotoxicity and apoptosis in pancreatic adenocarcinoma cell lines. 1838 57

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to induce mitochondrial apoptotic signaling that can be negatively regulated by prosurvival Bcl-2 proteins. ABT-737 is a small-molecule BH3 mimetic that binds to and antagonizes Bcl-2/Bcl-x(L) but not Mcl-1. We show that ABT-737 can synergistically enhance TRAIL-mediated cytotoxicity in human pancreatic cancer cell lines. ABT-737 was shown to enhance TRAIL-induced apoptosis as shown by DNA fragmentation, activation of caspase-8 and Bid, and cleavage of caspase-3 and poly(ADP-ribose) polymerase. A Bax conformational change induced by TRAIL was enhanced by ABT-737. ABT-737 disrupted the interaction of Bak with Bcl-x(L) in both cell lines. Furthermore, ABT-737 untethered the proapoptotic BH3-only protein Bim from its sequestration by Bcl-x(L) or Bcl-2. Bim small hairpin RNA (shRNA) was shown to attenuate caspase-3 cleavage and to reduce the cytotoxic effects of TRAIL plus ABT-737 compared with shRNA control cells. Finally, Mcl-1 shRNA potentiated caspase-3 cleavage by ABT-737 and enhanced its cytotoxic effects. Taken together, ABT-737 augments TRAIL-induced cell killing by unsequestering Bim and Bak and enhancing a Bax conformational change induced by TRAIL. These findings suggest a novel strategy to enhance cross-talk between the extrinsic and intrinsic apoptotic pathways to improve therapeutic efficacy against pancreatic cancer.
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PMID:BH3 mimetic ABT-737 potentiates TRAIL-mediated apoptotic signaling by unsequestering Bim and Bak in human pancreatic cancer cells. 1841 64

An in vitro, rapid, and quantitative cell-based assay is needed to predict the efficacy of cancer drugs in individual patients, because a cancer patient may have unconventional aspects of tumor development. Here we report a rapid and label-free quantitative method for verifying apoptosis in living cancer cells cultured on a sensor chip with a newly developed high-precision surface plasmon resonance (SPR) sensor. The time-course cell reaction was monitored as the SPR angle change rate for 5 min during a 35-min cell culture of pancreatic cancer lines with a drug. The time-course cell reaction was significantly related to cell viability counted after 48 h as assessed by caspase-3 activity assay of apoptosis. Furthermore, the detected SPR signal was derived from the decrease in inner mitochondrial membrane potential. The results obtained are universally valid for various cancer drugs mediating apoptosis through different cell-signaling pathways and even for combined use in various pancreatic cancer cell lines. This system can be applied in a clinical setting to evaluate the personal therapeutic potential of drugs including pharmacodynamic interactions.
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PMID:Rapid and quantitative method for evaluating the personal therapeutic potential of cancer drugs. 1848 Oct 47

In the present study, we investigated the effect of voluntary exercise on the formation and growth of the human pancreas Panc-1 and prostate PC-3 tumors in immunodeficient mice. Female severe combined immunodeficient (SCID) mice were injected subcutaneously with human pancreatic cancer Panc-1 cells, and male SCID mice were injected subcutaneously with human prostate cancer PC-3 cells. Voluntary running wheel exercise for 63 days, starting one week before the subcutaneous injection of Panc-1 or PC-3 tumor cells into SCID mice, suppressed the growth of Panc-1 and PC-3 tumors. The exercise regimen increased the food and fluid consumption in the female and male mice. Exercise also decreased the size of the parametrial fat pads in the female mice and the paradidymis fat pads in the male mice, but there was no effect on the body weight. Mechanistic studies showed that voluntary running wheel exercise inhibited proliferation as reflected by a decreased mitosis, and the exercise regimen also stimulated apoptosis as reflected by the increased caspase-3 (active form) expression in the Panc-1 and PC-3 tumors. Voluntary running wheel exercise decreased the ratio of the percent mitotic cells/apoptotic cells in Panc-1 and PC-3 tumors by 38 and 32%, respectively. The present study demonstrated an inhibitory effect of voluntary exercise on the growth of pancreas and prostate tumors in a SCID mouse xenograft model.
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PMID:Inhibitory effect of voluntary running wheel exercise on the growth of human pancreatic Panc-1 and prostate PC-3 xenograft tumors in immunodeficient mice. 1849 69

Resistance to apoptosis is a hallmark of pancreatic cancer, a leading cause of cancer deaths. Therefore, novel strategies are required to target apoptosis resistance. Here, we report that the combination of X-linked inhibitor of apoptosis (XIAP) inhibition and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an effective approach to trigger apoptosis despite Bcl-2 overexpression and to suppress pancreatic cancer growth in vitro and in vivo. Knockdown of XIAP by RNA interference cooperates with TRAIL to induce caspase activation, loss of mitochondrial membrane potential, cytochrome c release, and apoptosis in pancreatic carcinoma cells. Loss of mitochondrial membrane potential and cytochrome c release are extensively inhibited by a broad range or caspase-3 selective caspase inhibitor and by RNAi-mediated silencing of caspase-3, indicating that XIAP inhibition enhances TRAIL-induced mitochondrial damage in a caspase-3-dependent manner. XIAP inhibition combined with TRAIL even breaks Bcl-2-imposed resistance by converting type II cells that depend on the mitochondrial contribution to the death receptor pathway to type I cells in which TRAIL-induced activation of caspase-3 and caspase-9 and apoptosis proceeds irrespective of high Bcl-2 levels. Most importantly, XIAP inhibition potentiates TRAIL-induced antitumor activity in two preclinical models of pancreatic cancer in vivo. In the chicken chorioallantoic membrane model, XIAP inhibition significantly enhances TRAIL-mediated apoptosis and suppression of tumor growth. In a tumor regression model in xenograft-bearing mice, XIAP inhibition acts in concert with TRAIL to cause even regression of established pancreatic carcinoma. Thus, this combination of XIAP inhibition plus TRAIL is a promising strategy to overcome apoptosis resistance of pancreatic cancer that warrants further investigation.
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PMID:Targeting XIAP bypasses Bcl-2-mediated resistance to TRAIL and cooperates with TRAIL to suppress pancreatic cancer growth in vitro and in vivo. 1882 53

Transforming growth factor-beta (TGF-beta)-Smad signaling pathway participates in the regulation of a variety of cellular activities. Unlike the high incidences of Smad4 mutation or deletion in pancreatic cancer and gastrointestinal cancers, Smad4 gene is seldom mutated or deleted in hepatocellular carcinoma (HCC). The role of TGF-beta-Smad4 signaling pathway in leading to carcinogenesis of liver cells remains unknown. In this study, we succeeded in silencing Smad4 using lentiviral-mediated Smad4 RNA interference (RNAi). We investigated the role of Smad4 in TGF-beta1-induced cell proliferation and apoptosis of HCC cell line SMMC-7721. We determined cell proliferation, apoptosis, and expression of p21, p16, p53 and caspase 3. Results showed that TGF-beta1 not only had a significant anti-proliferation effect but also induced cellular apoptosis in SMMC-7721 cells. These effects induced by TGF-beta1 were almost completely blocked by the knockdown of Smad4. Western blot analysis revealed that p16 was up-regulated and caspase 3 was activated by silencing of Smad4, and the expression of p21 and wild-type p53 were not affected. These results suggest that TGF-beta1-induced cell growth inhibition by up-regulating p16 expression and cellular apoptosis by activating caspase 3 was Smad4-dependent. Additionally, the knock down of a specific gene using lentiviral-mediated RNAi appears to be a promising tool and strategy for analyzing endogenous gene function.
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PMID:Lentiviral-mediated Smad4 RNAi induced anti-proliferation by p16 up-regulation and apoptosis by caspase 3 down-regulation in hepatoma SMMC-7721 cells. 1894 1

Pancreatic cancer is one of the most common invasive malignancies and the fourth leading cause of cancer related mortality in U.S., thus developing new strategies to control pancreatic cancer is an important mission. We investigated the mechanism of capsaicin, the major pungent ingredient of red-chili pepper, in inducing apoptosis in pancreatic cancer cells. Treatment of AsPC-1 and BxPC-3 cells with capsaicin resulted in a dose-dependent inhibition of cell-viability and induction of apoptosis which was associated with the generation of ROS and persistent disruption of mitochondrial membrane potential. These effects were significantly blocked when the cells were pretreated with a general antioxidant N-acetyl cysteine (NAC). Exposure of AsPC-1 and BxPC-3 cells to capsaicin was also associated with increased expression of Bax, down-regulation of bcl-2, survivin and significant release of cytochrome c and AIF in the cytosol. On the contrary, above-mentioned effects were not observed in the normal acinar cells in response to capsaicin-treatment. Capsaicin-treatment resulted in the activation of JNK and JNK inhibitor SP600125 afforded protection against capsaicin-induced apoptosis. Furthermore, capsaicin when given orally markedly suppressed the growth of AsPC-1 pancreatic tumor xenografts in athymic nude mice, without side effects. Tumors from capsaicin treated mice demonstrated increased apoptosis, which was related to the activation of JNK and increased cytosolic protein expression of Bax, cytochrome c, AIF and cleaved caspase-3, as compared with controls. Taken together, these results show that capsaicin is an effective inhibitor of in vitro and in vivo growth of pancreatic cancer cells. These findings provide the rationale for further clinical investigation of capsaicin against pancreatic cancer.
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PMID:In vitro and in vivo induction of apoptosis by capsaicin in pancreatic cancer cells is mediated through ROS generation and mitochondrial death pathway. 1900 86

The transcriptional regulator TBX2 is genetically amplified in several cancers and has, in addition, important roles in development. In carcinogenesis, TBX2 regulates the cell cycle by suppressing the expression of cyclin-dependent kinase (CDK) inhibitors and destabilizes p53 by suppressing expression of ARF. In embryogenesis, however, TBX2 appears to act independently of the cell cycle or p53 and is regulated by growth factors. Tumorigenic functions of TBX2 that are independent of p53 or cell cycle regulation remain poorly understood. Here we used SW13 carcinoma cells which express inactive p53 and have no detectable p16 or p21 CDK-inhibitors as a model to study these functions. Expression of TBX2 in SW13 cells had no effect on the cell cycle but promoted anchorage-independence and increased resistance to apoptotic stimuli including UV-irradiation, the cytotoxic drug doxorubicin and lethal endoplasmic-reticulum stress. This is a cell type-dependent effect as TBX2 overexpression in PANC1 pancreatic cancer cells which are p53-negative has no effect on colony formation or survival after irradiation. Mechanistically, in SW13 cells, TBX2 overexpression strongly reduced the activation of caspase 3, 8 and 9 following UV-irradiation but without altering the expression of the corresponding procaspases. There were, however, dramatic and specific decreases in the expression of procaspases 1 and 4. The expression of the inhibitor of apoptosis, cIAP2/BIRC3, increased in TBX2-overexpressing cells. TBX2 was upregulated in a PI3K-dependent manner by growth factors that are tumorigenic for SW13. Inhibition of Akt phosphorylation abrogates upregulation of TBX2 by FGF-4. Our findings identify TBX2 as a cell type-dependent survival factor under a p53-negative background, and are indicative of a potentially wider role for TBX2 in carcinogenesis than hitherto described.
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PMID:Expression of TBX2 promotes anchorage-independent growth and survival in the p53-negative SW13 adrenocortical carcinoma. 1921 23

Evasion of apoptosis is a characteristic feature of pancreatic cancer, a prototypic cancer that is refractory to current treatment approaches. Hence, there is an urgent need to design rational strategies that counter apoptosis resistance. To explore X-linked inhibitor of apoptosis (XIAP) as a therapeutic target in pancreatic cancer, we analyzed the expression of XIAP in pancreatic tumor samples and evaluated the effect of small molecule XIAP inhibitors alone and in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against pancreatic carcinoma in vitro and in vivo. Here, we report that XIAP is highly expressed in pancreatic adenocarcinoma samples compared with normal pancreatic ducts. Small molecule XIAP inhibitors synergize with TRAIL to induce apoptosis and to inhibit long-term clonogenic survival of pancreatic carcinoma cells. In contrast, they do not reverse the lack of toxicity of TRAIL on nonmalignant cells in vitro or normal tissues in vivo, pointing to a therapeutic index. Most importantly, XIAP inhibitors cooperate with TRAIL to trigger apoptosis and suppress pancreatic carcinoma growth in vivo in two preclinical models, i.e., the chorioallantoic membrane model and a mouse xenograft model. Parallel immunohistochemical analysis of tumor tissue under therapy reveals that the XIAP inhibitor acts in concert with TRAIL to cause caspase-3 activation and apoptosis. In conclusion, our findings provide, for the first time, evidence in vivo that XIAP inhibitors prime pancreatic carcinoma cells for TRAIL-induced apoptosis and potentiate the antitumor activity of TRAIL against established pancreatic carcinoma. These findings build the rationale for further (pre)clinical development of XIAP inhibitors and TRAIL against pancreatic cancer.
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PMID:Small molecule XIAP inhibitors enhance TRAIL-induced apoptosis and antitumor activity in preclinical models of pancreatic carcinoma. 1925 13


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