Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was undertaken to gain insights into the molecular mechanism of apoptosis induction by phenethyl isothiocyanate (PEITC), which is a cancer chemopreventive constituent of cruciferous vegetables, using PC-3 human prostate cancer cells as a model. The PEITC-induced cell death in PC-3 cells was associated with disruption of the mitochondrial membrane potential, release of apoptogenic molecules (cytochrome c and Smac/DIABLO) from mitochondria to the cytosol and generation of reactive oxygen species (ROS), which were blocked in the presence of a combined mimetic of superoxide dismutase and catalase (Euk134). Ectopic expression of Bcl-xL, whose protein level is reduced markedly on treatment of PC-3 cells with PEITC, conferred partial protection against PEITC-induced apoptosis only at higher drug concentrations (>10 microM). Administration of 12 micromol PEITC/day (Monday through Friday) by oral gavage significantly retarded growth of PC-3 xenografts in athymic mice. For instance, 31 days after the initiation of PEITC administration, the average tumor volume in control mice (721 +/- 153 mm3) was approximately 2-fold higher compared with mice receiving 12 micromol PEITC/day. The PEITC-mediated inhibition of PC-3 xenograft growth was associated with induction of Bax and Bid proteins. In conclusion, the present study indicates that the PEITC-induced apoptosis in PC-3 cells is mediated by ROS-dependent disruption of the mitochondrial membrane potential and regulated by Bax and Bid.
Carcinogenesis 2006 Nov
PMID:Phenethyl isothiocyanate-induced apoptosis in PC-3 human prostate cancer cells is mediated by reactive oxygen species-dependent disruption of the mitochondrial membrane potential. 1677 48

All tumors examined to date contain mutations in mitochondrial DNA (mtDNA). In addition, depletion of mtDNA is reported in a variety of tumors. Mitochondrial dysfunction resulting from changes in mtDNA invokes mitochondria-to-nucleus retrograde response in human cells. To identify proteins involved in retrograde response and their potential role in tumorigenesis, we carried out a comparative proteomic analysis using a cell line in which the mitochondrial genome was completely depleted (rho(0) cells lacking all mtDNA-encoded protein subunits), a cybrid cell line in which mtDNA was restored, and the parental cell line. Our comparative proteomic approach revealed marked changes in the cellular proteome and led us to identify quantitative changes in expression of several proteins. We found that subunits of complex I and complex III, molecular chaperones, and a protein involved in cell cycle control were downregulated and Inosine 5'-monophosphate dehydrogenase type 2 (IMPDH2) involved in nucleotide biosynthesis was upregulated in rho(0) cells. Our findings demonstrate that the expression of proteins is restored to wild type level by transfer of wild type mitochondria to rho(0) cells, suggesting that these proteins play key roles in retrograde response. To determine a potential role for identified retrograde responsive proteins in tumorigenesis, we analyzed the expression of UQCRC1 gene (encoding ubiquinol cytochrome-c reductase core protein I) in breast and ovarian tumors. We found that (1) UQCRC1 was highly expressed in breast (74%) and ovarian tumors (34%) and (2) the expression positively correlated with cytochrome c-oxidase (COXII) encoded by mtDNA. Our study opens an avenue for identification of retrograde proteins as potential tumor suppressors or oncogenes involved in carcinogenesis.
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PMID:Proteomic analysis of mitochondria-to-nucleus retrograde response in human cancer. 1696 84

Silibinin, a natural flavonolignan, induces apoptosis in human bladder transitional-cell papilloma RT4 cells both in vitro and in vivo; however, mechanisms of such efficacy are not completely identified. Here, we studied the mechanisms involved in silibinin-induced apoptosis of RT4 cells having intact p53. Silibinin increased p53 protein level together with its increased phosphorylation at serine 15, activated caspase cascade and caused Bid cleavage for apoptosis. Silibinin-caused p53 activation was mediated via ATM-Chk2 pathway, which in turn induced caspase 2-mediated apoptosis. Pifithrin-alpha, a p53 inhibitor, reversed silibinin-induced caspase activation including caspase 2; however, caspase 2 inhibitor also reversed p53 phosphorylation suggesting a bidirectional regulation between them. Further, silibinin caused a rapid translocation of p53 and Bid into mitochondria leading to increased permeabilization of mitochondrial membrane and cytochrome c release into the cytosol. JNK1/2 activation was observed as a connecting link for p53-mediated caspase 2 activation. Interestingly, silibinin-induced apoptosis was mediated, in part, via Cip1/p21 cleavage by caspase, which was reversed by Cip1/p21 siRNA. Together, these results suggested the novel mechanisms for apoptosis induction by silibinin involving p53-caspase 2 activation and caspase-mediated cleavage of Cip1/p21.
Carcinogenesis 2006 Nov
PMID:Silibinin activates p53-caspase 2 pathway and causes caspase-mediated cleavage of Cip1/p21 in apoptosis induction in bladder transitional-cell papilloma RT4 cells: evidence for a regulatory loop between p53 and caspase 2. 1677 94

Aspirin and other nonsteroidal anti-inflammatory drugs inhibit cell proliferation and induce apoptosis in various cancer cell lines, which is considered to be an important mechanism for their anti-tumor activity and prevention of carcinogenesis. However, the molecular mechanisms through which these compounds induce apoptosis are not well understood. Here we have found that aspirin treatment of the mouse Neuro 2a cells impaired the proteasome function and caused severe mitochondrial abnormalities. Treatment with aspirin lead to a dose- and time-dependent decrease in proteasome activity and an increase in the accumulation of ubiquitylated proteins in the cells, which correlated with its effect on cell death. Aspirin exposure also resulted in an increase in the half-life of pd1EGFP, a model substrate of proteasome, as well as various intracellular substrates like Bax, IkappaB-alpha, p53, and p27(kip1). Aspirin-induced proteasomal malfunction might be responsible, at least in part, for the down-regulation of NF-kappaB activity and neurite outgrowth. Finally, we have shown that aspirin treatment caused changes in the mitochondrial membrane potential, release of cytochrome c from mitochondria, and activation of caspase-9 and -3, which could be because of the proteasomal dysfunction.
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PMID:Aspirin induces apoptosis through the inhibition of proteasome function. 1688 Feb 2

Stress-induced heat shock protein 70 (Hsp70) effectively protects cells against apoptosis, although the anti-apoptotic mechanism is still undefined. Exposure of human melanocytes to heat and subsequent UVB irradiation increased the level of Hsp70 and pre-heating reduced UVB induced apoptosis. Immunofluorescence staining of Hsp70 in combination with staining of lysosomes (Lamp2) or mitochondria (Mitotracker) in pre-heated UVB exposed cells showed co-localization of Hsp70 with both lysosomes and mitochondria in the surviving cell population. Furthermore, UVB induced apoptosis was accompanied by lysosomal and mitochondrial membrane permeabilization, detected as release of cathepsin D and cytochrome c, respectively, which were prevented by heat pre-treatment. In purified fractions of lysosomes and mitochondria, recombinant Hsp70 attached to both lysosomal and mitochondrial membranes. Moreover, in apoptotic cells Bax was translocated from a diffuse cytosolic location into punctate mitochondrial-like structures, which was inhibited by Hsp70 induction. Such inhibition of Bax translocation was abolished by transfection with Hsp70 siRNA. Furthermore, Hsp70 siRNA eliminated the apoptosis preventive effect observed after pre-heating. These findings show Hsp70 to rescue melanocytes from UVB induced apoptosis by preventing release of cathepsins from lysosomes, Bax translocation and cytochrome c release from mitochondria.
Carcinogenesis 2007 Mar
PMID:Hsp70 protects against UVB induced apoptosis by preventing release of cathepsins and cytochrome c in human melanocytes. 1695 Jul 97

In human colorectal cancer cells, the polyphenol resveratrol (RV) activated the caspase-dependent intrinsic pathway of apoptosis. This effect was not mediated via estrogen receptors. Pepstatin A, an inhibitor of lysosomal cathepsin D (CD), not (2S,3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane ethyl ester, an inhibitor of cathepsins B and L, prevented RV cytotoxicity. Similar protection was attained by small interference RNA-mediated knockdown of CD protein expression. RV promoted the accumulation of mature CD, induced lysosome leakage and increased cytosolic immunoreactivity of CD. Inhibition of CD or its post-transcriptional down-regulation precluded Bax oligomerization, permeabilization of mitochondrial membrane, cytosolic translocation of cytochrome c, caspase 3 activation and terminal deoxinucleotidyl transferase-mediated dUTP-biotin nick end labeling positivity occurring in RV-treated cells. The present study identifies the lysosome as a novel target of RV activity and demonstrates a hierarchy of the proteolytic pathways involved in its cytotoxic mechanism in which the lysosomal CD acts upstream of the cytosolic caspase activation. Our data indicate that metabolic, pharmacologic or genetic conditions affecting CD expression and/or activity could reflect on the sensitivity of cancer cells to RV.
Carcinogenesis 2007 May
PMID:Resveratrol induces cell death in colorectal cancer cells by a novel pathway involving lysosomal cathepsin D. 1711 25

The role of the gastrin peptide hormones (G17, G34) and their precursors (progastrins, PG; gly-extended gastrin, G-gly), in gastrointestinal (GI) cancers has been extensively reviewed in recent years [W. Rengifo-Cam, P. Singh, Role of progastrins and gastrins and their receptors in GI and pancreatic cancers: targets for treatment, Curr. Pharm. Des. 10 (19) (2004) 2345-2358; M. Dufresne, C. Seva, D. Fourmy, Cholecystokinin and gastrin receptors, Physiol. Rev. 86 (3) (2006) 805-847; A. Ferrand, T.C. Wang, Gastrin and cancer: a review, Cancer Lett. 238 (1) (2006) 15-29]. A possible important role of progastrin peptides in colon carcinogenesis has become evident from experiments with transgenic mouse models [W. Rengifo-Cam, P. Singh, (2004); A. Ferrand, T.C. Wang, (2006)]. It is now known that growth stimulatory and co-carcinogenic effects of gastrin/PG peptides are mediated by both proliferative and anti-apoptotic effects of the peptides on target cells [H. Wu, G.N. Rao, B. Dai, P. Singh, Autocrine gastrins in colon cancer cells Up-regulate cytochrome c oxidase Vb and down-regulate efflux of cytochrome c and activation of caspase-3, J. Biol. Chem. 275 (42) (2000) 32491-32498; H. Wu, A. Owlia, P. Singh, Precursor peptide progastrin(1-80) reduces apoptosis of intestinal epithelial cells and upregulates cytochrome c oxidase Vb levels and synthesis of ATP, Am. J. Physiol. Gastrointest. Liver Physiol. 285 (6) (2003) G1097-G1110]. Several receptor subtypes have been described that mediate growth effects of gastrin peptides [W. Rengifo-Cam, P. Singh (2004); M. Dufresne, C. Seva, D. Fourmy, (2006)]. Recently, we identified Annexin II as a high affinity binding protein for gastrin/PG peptides [P. Singh, H. Wu, C. Clark, A. Owlia, Annexin II binds progastrin and gastrin-like peptides, and mediates growth factor effects of autocrine and exogenous gastrins on colon cancer and intestinal epithelial cells, Oncogene (2006), doi:10.1038/sj.onc.1209798]. Importantly, the expression of Annexin II was required for mediating growth stimulatory effects of gastrin and PG peptides on intestinal epithelial and colon cancer cells [P. Singh, H. Wu, C. Clark, A. Owlia, Annexin II binds progastrin and gastrin-like peptides, and mediates growth factor effects of autocrine and exogenous gastrins on colon cancer and intestinal epithelial cells, Oncogene (2006), doi:10.1038/sj.onc.1209798], suggesting that Annexin-II may represent the elusive novel receptor for gastrin/PG peptides. The importance of this finding in relation to the structure and function of Annexin-II, especially in GI cancers, is described below. Since this surprising finding represents a new front in our understanding of the mechanisms involved in mediating growth effects of gastrin/PG peptides in GI cancers, our current understanding of the role of Annexin-II in proliferation and metastasis of cancer cells is additionally reviewed.
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PMID:Role of Annexin-II in GI cancers: interaction with gastrins/progastrins. 1718 24

Curcumin, an active ingredient of turmeric (Curcuma longa), inhibits proliferation and induces apoptosis in cancer cells, but the sequence of events leading to cell death is poorly defined. The objective of this study was to examine the molecular mechanisms by which multidomain pro-apoptotic Bcl-2 family members Bax and Bak regulate curcumin-induced apoptosis using mouse embryonic fibroblasts (MEFs) deficient in Bax, Bak or both genes. Curcumin treatment resulted an increase in the protein levels of both Bax and Bak, and mitochondrial translocation and activation of Bax in MEFs to trigger drop in mitochondrial membrane potential, cytosolic release of apoptogenic molecules [cytochrome c and second mitochondria-derived activator of caspases (Smac)/direct inhibitor of apoptosis protein-binding protein with low isoelectric point], activation of caspase-9 and caspase-3 and ultimately apoptosis. Furthermore, MEFs derived from Bax and Bak double-knockout (DKO) mice exhibited even greater protection against curcumin-induced release of cytochrome c and Smac, activation of caspase-3 and caspase-9 and induction of apoptosis compared with wild-type MEFs or single-knockout Bax(-/-) or Bak(-/-) MEFs. Interestingly, curcumin treatment also caused an increase in the protein level of apoptosis protease-activating factor-1 in wild-type MEFs. Smac N7 peptide enhanced curcumin-induced apoptosis, whereas Smac siRNA inhibited the effects of curcumin on apoptosis. Mature form of Smac sensitized Bax and Bak DKO MEFs to undergo apoptosis by acting downstream of mitochondria. The present study demonstrates the role of Bax and Bak as a critical regulator of curcumin-induced apoptosis and over-expression of Smac as interventional approaches to deal with Bax- and/or Bak-deficient chemoresistant cancers for curcumin-based therapy.
Carcinogenesis 2007 Jun
PMID:Bax and Bak genes are essential for maximum apoptotic response by curcumin, a polyphenolic compound and cancer chemopreventive agent derived from turmeric, Curcuma longa. 1727 31

To isolate pharmacologically safe compounds that can induce apoptosis of tumor cells, leaves of an aromatic plant (Zanthoxylum schinifolium), which are widely used as a food flavor and herbal medicine in Korea and Japan, were sequentially extracted by organic solvents. An apoptogenic ingredient in the methylene chloride extract was further purified by silica gel column chromatography and identified as auraptene (AUR). The IC(50) value of AUR against Jurkat T cells was 16.5 microg/ml. After the treatment of Jurkat T cells with AUR, the endoplasmic reticulum (ER) stress-mediated activation of caspase-12 and -8 and subsequent apoptotic events including c-Jun N-terminal kinase (JNK) activation, cleavage of FLICE inhibitory protein and Bid, mitochondrial cytochrome c release, activation of caspase-9 and -3, degradation of poly (ADP-ribose) polymerase and apoptotic DNA fragmentation were induced in a dose-dependent manner. The cytotoxicity of AUR was not blocked by the anti-Fas neutralizing antibody ZB-4. The AUR-induced cytotoxicity and apoptotic events were abrogated by ectopic over-expression of Bcl-xL or addition of the pan-caspase inhibitor z-VAD-fmk. The individual or simultaneous addition of the m-calpain inhibitor (E64d), JNK inhibitor (SP600125) and mitochondrial permeability transition pore inhibitor (CsA) failed to prevent apoptotic events including caspase-8 activation and Bid cleavage, unless the caspase-8 inhibitor (z-IETD-fmk) was combined, whereas AUR-induced caspase-12 activation was sustained even in the concomitant presence of z-IETD-fmk. These results demonstrated that the apoptotic effect of AUR on Jurkat T cells was exerted by the ER stress-mediated activation of caspase-8, and the subsequent induction of mitochondria-dependent or -independent activation of caspase cascade, which could be suppressed by Bcl-xL.
Carcinogenesis 2007 Jun
PMID:Apoptogenic activity of auraptene of Zanthoxylum schinifolium toward human acute leukemia Jurkat T cells is associated with ER stress-mediated caspase-8 activation that stimulates mitochondria-dependent or -independent caspase cascade. 1730 Oct 64

Flavonoids are polyphenolic compounds that are ubiquitously in plants and display a vast array of biological activities. Here we have studied the effect of the phenylbenzo-gamma-pyrone-derivative quercetin 3-methyl ether tetracetate (QD), obtained by acetylation of the natural product quercetin 3-methyl ether, on cell viability of human leukemia HL-60 and U937 cell lines. The results show that QD was cytotoxic and induced G2-M phase cell cycle arrest on both cell lines and it was a potent apoptotic inducer on HL-60 cells. QD-induced apoptosis is (i) mediated by caspase activation, since it was prevented by the non-specific caspase inhibitor z-VAD-fmk, (ii) associated with cytochrome c release and (iii) triggered in Bcl-2 over-expressing U937 cells. The treatment of HL-60 and U937 cells with QD also induces the activation of the mitogen-activated protein kinases (MAPKs) pathway, including c-Jun N-terminal kinase, p38 mitogen-activated protein kinase and extracellular signal-regulated kinases (ERK) 1/2. Inhibition of c-Jun N-terminal kinase by SP600125 and of p38 mitogen-activated protein kinase by SB203580 had no influence on QD-mediated apoptosis. In contrast, inhibition of ERK1/2 with the pharmacologic inhibitors U0126 or PD98059, together with QD, resulted in an important enhancement of apoptosis. Cells are sensitized to QD-mediated apoptosis after blocking ERK1/2, which suggests that inhibition of this pathway is a valuable strategy to increase the sensitivity of human leukemia HL-60 cells toward QD.
Carcinogenesis 2007 Oct
PMID:Acetyl derivative of quercetin 3-methyl ether-induced cell death in human leukemia cells is amplified by the inhibition of ERK. 1754 1


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