Molecular Carcinogenesis
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Diallyl trisulfide‐induced apoptosis in human cancer cells is linked to checkpoint kinase 1‐mediated mitotic arrest Abstract Growth suppressive effect of diallyl trisulfide (DATS), a promising cancer chemopreventive constituent of garlic, against cultured human cancer cells correlates with checkpoint kinase 1 (Chk1)‐mediated mitotic arrest, but the fate of the cells arrested in mitosis remains elusive. Using LNCaP and HCT‐116 human cancer cells as a model, we now demonstrate that the Chk1‐mediated mitotic arrest resulting from DATS exposure leads to apoptosis. The DATS exposure resulted in G2 phase and mitotic arrest in both LNCaP and HCT‐116 cell lines. The G2 arrest was accompanied by downregulation of cyclin‐dependent kinase 1 (Cdk1), cell division cycle (Cdc) 25B, and Cdc25C leading to Tyr15 phosphorylation of Cdk1 (inactivation). The DATS‐mediated mitotic arrest correlated with inactivation of anaphase‐promoting complex/cyclosome as evidenced by accumulation of its substrates cyclinB1 and securin. The DATS treatment increased activating phosphorylation of Chk1 (Ser317) and transient transfection with Chk1‐targeted siRNA conferred significant protection against DATS‐induced mitotic arrest in both cell lines. The Chk1 protein knockdown also afforded partial yet statistically significant protection against apoptotic DNA fragmentation and caspase‐3 activation resulting from DATS exposure in both LNCaP and HCT‐116 cells. Even though DATS treatment resulted in stabilization and Ser15 phosphorylation of p53, the knockdown of p53 protein failed to rescue DATS‐induced mitotic arrest. In conclusion, the results of the present study indicate that Chk1 dependence of DATS‐induced mitotic arrest in human cancer cells is not influenced by the p53 status and cells arrested in mitosis upon DATS exposure are driven to apoptotic DNA fragmentation. © 2009 Wiley‐Liss, Inc.
Molecular Carcinogenesis - Tập 48 Số 11 - Trang 1018-1029 - 2009
Ki‐<i>ras</i> oncogene mutations in tumors and DNA adducts formed by benz[<i>j</i>]aceanthrylene and benzo[<i>a</i>]pyrene in the lungs of strain A/J mice Abstract Strain A/J mice received intraperitoneal injections of benz[j ]aceanthrylene (B[j ]A) or benzo[a ]pyrene (B[a ]P). At 24, 48, and 72 h, lung tissues were removed for analysis of B[a ]P‐ or B[j ]A‐derived DNA adduct formation during the first 3 d of exposure. One group of mice exposed to these hydrocarbons was kept for 8 mo to determine lung tumor multiplicity, the occurrence of mutations in codons 12 and 61 of the Ki‐ras gene in the tumors that arose, the relationship between Ki‐ras oncogene mutations in tumors, and the presence and quantity of genomic DNA adducts. The major DNA adduct in the lungs of mice exposed to B[a ]P was N 2 ‐(10β‐[ + B,7α, 9α‐trihydroxy‐7,8,9,10‐tetrahydrobenzo[a ]pyrene]yl)‐deoxyguanosine (BPDE‐l‐dGuo) arising from bay‐region diolepoxide activation of B[a ]P and was consistent with the occurrence of tumors with mutations GGT → TGT (56%), GGT → GTT (25%), and GGT → GAT (19%) in codon 12, all involving mutations of a guanine. B[j ]A, a demethylated analogue of 3‐methylcholanthrene (3‐MCA) with an unsaturated cyclopenta ring, produced 16‐ to 60‐fold more tumors at equivalent doses than did B[a ]P; the mutations in tumors were GGT → TGT (4%), GGT → GTT (30%), and GGT → CGT (65%). Analysis of adduction patterns in DNA suggested that B[j ]A was activated to form DNA‐binding derivatives in A/J mouse lungs primarily at the cyclopenta ring even though B[j ]A contains a bay region. As reported in the published literature, the mutation spectrum induced by 3‐MCA in Ki‐ras codon 12 of mouse cells is similar to that of B[a ]P but not to that of its close relative B[j ]A. In contrast to B[j ]A, 3‐MCA is activated mostly via a bay‐region diol‐epoxide since its cyclopenta ring is saturated and not easily epoxidated. Therefore, we propose that the GGT → CGT mutations produced by B[j ]A in Ki‐ras codon 12 were mostly the result of cyclopentaring‐derived adducts.
Molecular Carcinogenesis - Tập 8 Số 3 - Trang 186-192 - 1993
Suppression of radiation‐induced neoplastic transformation by overexpression of mitochondrial superoxide dismutase Abstract Manganese superoxide dismutase (MnSOD) scavenges toxic superoxide radicals produced in the mitochondria. Transfection of the human MnSOD gene into mouse C3H 10T1/2 cells resulted in production of active MnSOD, which was properly transported into mitochondria. Overexpression of MnSOD protected cells from radiation‐, but not chemically‐induced neoplastic transformation. This finding demonstrates that oxidative stress that occurs in the mitochondria plays an important role in the development of neoplastic transformation. © 1992 Wiley‐Liss, Inc.
Molecular Carcinogenesis - Tập 6 Số 4 - Trang 238-242 - 1992
BRCA1 and acetyl‐CoA carboxylase: The metabolic syndrome of breast cancer Abstract Breast cancer‐associated mutations affecting the highly‐conserved C‐terminal BRCT domains of the tumor suppressor gene br east ca ncer susceptibility gene 1 (BRCA1) fully disrupt the ability of BRCA1 to interact with a cetyl c oenzyme A c arboxylase a lpha (ACCA), the rate‐limiting enzyme catalyzing de novo fatty acid biogenesis. Specifically, BRCA1 interacts solely with the phosphorylated (inactive) form of ACCA (P‐ACCA), and the formation of the BRCA1/P‐ACCA complex interferes with ACCA activity by preventing P‐ACCA dephosphorylation. One of the hallmarks of aggressive cancer cells is a high rate of energy‐consuming anabolic processes driving the synthesis of lipids, proteins, and DNA (all of which are regulated by the energy status of the cell). The ability of BRCA1 to stabilize the phosphorylated/inactive form of ACCA strongly suggests that the tumor suppressive function of BRCA1 closely depends on its ability to mimic a cellular‐low‐energy status, which is known to block tumor cell anabolism and suppress the malignant phenotype. Interestingly, physical exercise and lack of obesity in adolescence have been associated with significantly delayed breast cancer onset for Ashkenazi Jewish women carrying BRCA1 gene mutations. Further clinical work may explore a chemopreventative role of “low‐energy‐mimickers” deactivating the ACCA‐driven “lipogenic phenotype” in women with inherited mutations in BRCA1. This goal might be obtained with current therapeutic approaches useful in treating the metabolic syndrome and associated disorders in humans (e.g., type 2 diabetes and obesity), including metformin, thiazolidinediones (TZDs), calorie deprivation, and exercise. Alternatively, new forthcoming ACCA inhibitors may be relevant in the management of BRCA1‐dependent breast cancer susceptibility and development. © 2007 Wiley‐Liss, Inc.
Molecular Carcinogenesis - Tập 47 Số 2 - Trang 157-163 - 2008
Pharmacological inhibition of fatty acid synthase (FAS): A novel therapeutic approach for breast cancer chemoprevention through its ability to suppress Her‐2/neu (erbB‐2) oncogene‐induced malignant transformation Abstract We designed our experiments to evaluate whether fatty acid synthase (FAS), a lipogenic enzyme linked to tumor virulence in population studies of human cancer, is necessary for the malignant transformation induced by Her‐2/neu (erbB‐2) oncogene, which is overexpressed not only in invasive breast cancer but also in premalignant atypical duct proliferations and in ductal carcinoma in situ of the breast. To avoid the genetic complexities associated with established breast cancer cell lines, we employed NIH‐3T3 mouse fibroblasts engineered to overexpress human Her‐2/neu coding sequence. NIH‐3T3/Her‐2 cells demonstrated a significant upregulation of FAS protein expression, which was dependent on the upstream activation of mitogen‐activated protein kinase and phosphatidylinositol 3′‐kinase/AKT pathways. Remarkably, pharmacological FAS blockade using the mycotoxin cerulenin or the novel small compound C75 completely suppressed the state of Her‐2/neu‐induced malignant transformation by inhibiting the ability of NIH‐3T3/Her‐2 cells to grow under either anchorage‐independent (i.e., to form colonies in soft agar) or low‐serum monolayer conditions. Moreover, NIH‐3T3/Her‐2 fibroblasts were up to three times more sensitive to chemical FAS inhibitors relative to untransformed controls as determined by MTT‐based cell viability assays. In addition, pharmacological FAS blockade preferentially induced apoptotic cell death of NIH‐3T3/Her‐2 fibroblasts, as determined by an ELISA for histone‐associated DNA fragments and by the terminal deoxynucleotidyltransferase (TdT)‐mediated nick end labeling assay (TUNEL). Interestingly, the degree of Her‐2/neu oncogene expression in a panel of breast cancer cell lines was predictive of sensitivity to chemical FAS inhibitors‐induced cytotoxicity, while low‐FAS expressing and chemical FAS inhibitors‐resistant MDA‐MB‐231 breast cancer cells became hypersensitive to FAS blockade when they were engineered to overexpress Her‐2/neu. Our observations strongly suggest that inhibition of FAS activity may provide a new molecular avenue for chemotherapeutic prevention and/or treatment of Her‐2/neu‐related breast carcinomas. © 2004 Wiley‐Liss, Inc.
Molecular Carcinogenesis - Tập 41 Số 3 - Trang 164-178 - 2004
KAI1, A prostate metastasis suppressor: Prediction of solvated structure and interactions with binding partners; integrins, cadherins, and cell‐surface receptor proteins† Abstract The solution structure of the transmembrane‐4 superfamily protein KAI1, a recently identified prostate cancer metastasis suppressor gene that encodes a 267–amino acid protein, was modeled. The structure of this four‐helical transmembrane protein was developed by defining and modeling sections individually. A complete three‐dimensional structure for the solvated protein was developed by combining the individually modeled sections. The four‐helix transmembrane bundle structure was predicted combining information from several methods including Fourier transform analysis of residue variability for helix orientation. The structure of the KAI1 large extracellular domain was modeled based on the solved crystal structure of the extracellular domain of another tetraspanin superfamily protein member, CD81 (hepatitis C virus envelope E2 glycoprotein receptor). This is a novel protein fold consisting of five alpha helices held together by two disulfide bonds for which the CD81 protein is the first solved representative. Molecular dynamics studies were performed to test stability and to relax the total model KAI1 structure's solution. The resulting KAI1 structural model should be a useful tool for predicting modes of self‐association and associations with other TM4SF proteins, integrins, cadherins, and other KAI1 binding partners. Mutations for probing the interactions of KAI1 with antibodies and with other binding partners are suggested. Published 2001 Wiley‐Liss, Inc.
Molecular Carcinogenesis - Tập 32 Số 3 - Trang 139-153 - 2001
Lysosomal destabilization and cathepsin B contributes for cytochrome <i>c</i> release and caspase activation in embelin‐induced apoptosis Abstract XIAP is an important antiapoptotic protein capable of conferring resistance to cancer cells. Embelin, the small molecular inhibitor of XIAP, possesses wide spectrum of biological activities with strong inhibition of nuclear factor kappa B and downstream antiapoptotic genes. However, the mechanism of its cell death induction is not known. Our studies using colon cancer cells lacking p53 and Bax suggest that both lysosomes and mitochondria are prominent targets of embelin‐induced cell death. Embelin induced cell‐cycle arrest in G1 phase through p21, downstream of p53. In the absence of p21, the cells are sensitized to death in a Bax‐dependent manner. The loss of mitochondrial membrane potential induced by embelin was independent of Bax and p53, but lysosomal integrity loss was strongly influenced by the presence of p53 but not by Bax. Lysosomal role was further substantiated by enhanced cathepsin B activity noticed in embelin‐treated cells. p53‐dependent lysosomal destabilization and cathepsin B activation contribute for increased sensitivity of p21‐deficient cells to embelin with enhanced caspase 9 and caspase 3 activation. Cathepsin B inhibitor reduced cell death and cytochrome c release in embelin‐treated cells indicating lysosomal pathway as the upstream of mitochondrial death signaling. Deficiency of cell‐cycle arrest machinery renders cells more sensitive to embelin with enhanced lysosomal destabilization and caspase processing emphasizing its potential therapeutic importance to address clinical drug resistance. © 2009 Wiley‐Liss, Inc.
Molecular Carcinogenesis - Tập 49 Số 4 - Trang 324-336 - 2010
Allelic loss at the tuberous sclerosis 2 locus in spontaneous tumors in the Eker rat Abstract Somatic events leading to the inactivation of tumor suppressor genes often involve chromosomal alterations that can be detected as loss of heterozygosity(a). In the Eker rat, spontaneous tumors of the kidney, uterus, and spleen develop as a result of a germline mutation of the tuberous sclerosis 2(Tsc2 ) gene. We examined the pattern and frequency of LOH at the predisposing locus in 77 primary tumors and cell lines to gain an understanding of the role of Tsc2 allelic loss in the pathogenesis of Eker‐derived tumors. Although most renal and uterine tumors(primary and cell lines) displayed LOH, splenic hemangiosarcomas did not. Although the presence of normal tissue may account for some of this difference, the possibility exists that an alternative mechanism, such as subtle mutation or gene dosage effects, may be involved during splenic tumorigenesis. Northern analysis confirmed that LOH resulted in loss of the wild‐type transcripts for the Tsc2 gene. Thus, the inactivation of both alleles plays an important role in renal and uterine tumor development, in keeping with Knudson's two‐hit hypothesis. In addition, renal tumors that retained the wild‐type allele also did not express the normal transcript, suggesting that the remaining Tsc2 alleles had acquired subtle mutations resulting in loss of gene function.© 1995 Wiley‐Liss, Inc
Molecular Carcinogenesis - Tập 14 Số 1 - Trang 28-36 - 1995
Transformation of kidney epithelial cells by a quinol thioether via inactivation of the tuberous sclerosis‐2 tumor suppressor gene Abstract Although hydroquinone (HQ) is a rodent carcinogen, because of its lack of mutagenicity in standard bacterial mutagenicity assays it is generally considered a nongenotoxic carcinogen. 2,3,5‐Tris ‐(glutathion‐S ‐yl)HQ (TGHQ) is a potent nephrotoxic metabolite of HQ that may play an important role in HQ‐mediated nephrocarcinogenicity. TGHQ mediates cell injury by generating reactive oxygen species and covalently binding to tissue macromolecules. We determined the ability of HQ and TGHQ to induce cell transformation in primary renal epithelial cells derived from the Eker rat. Eker rats possess a germline inactivation of one allele of the tuberous sclerosis‐2 (Tsc‐2 ) tumor suppressor gene that predisposes the animals to renal cell carcinoma. Treatment of primary Eker rat renal epithelial cells with HQ (25 and 50 μM) or TGHQ (100 and 300 μM) induced 2‐ to 4‐fold and 6‐ to 20‐fold increases in cell transformation, respectively. Subsequently, three cell lines (The QT‐RRE 1, 2, and 3) were established from TGHQ‐induced transformed colonies. The QT‐RRE cell lines exhibited a broad range of numerical cytogenetic alterations, loss of heterozygosity at the Tsc‐2 gene locus, and loss of expression of tuberin, the protein encoded by the Tsc‐2 gene. Only heterozygous (Tsc ‐2 EK/+ ) kidney epithelial cells were susceptible to transformation by HQ and TGHQ, as wild‐type cells (Tsc‐2 +/+ ) showed no increase in transformation frequency over background levels following chemical exposure. These data indicate that TGHQ and HQ are capable of directly transforming rat renal epithelial cells and that the Tsc‐ 2 tumor suppressor gene is an important target of TGHQ‐mediated renal epithelial cell transformation. © 2001 Wiley‐Liss, Inc.
Molecular Carcinogenesis - Tập 31 Số 1 - Trang 37-45 - 2001
Molecular mechanisms of Nrf2‐mediated antioxidant response Abstract Nrf2 is the key transcription factor regulating the antioxidant response. Nrf2 signaling is repressed by Keap1 at basal condition and induced by oxidative stress. Keap1 is recently identified as a Cullin 3‐dependent substrate adaptor protein. A two‐sites binding “hinge & latch” model vividly depicts how Keap1 can efficiently present Nrf2 as substrate for ubiquitination. Oxidative perturbation can impede Keap1‐mediated Nrf2 ubiquitination but fail to disrupt Nrf2/Keap1 binding. Nrf2 per se is a redox‐sensitive transcription factor. A new Nrf2‐mediated redox signaling model is proposed based on these new discoveries. Free floating Nrf2 protein functions as a redox‐sensitive probe. Keap1 instead functions as a gate keeper to control the availability of Nrf2 probes and thus regulates the overall sensitivity of the redox signaling. © 2008 Wiley‐Liss, Inc.
Molecular Carcinogenesis - Tập 48 Số 2 - Trang 91-104 - 2009
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