Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Epidemiological studies recently concluded that consumption of cruciferous vegetables such as broccoli, cabbage, and cauliflower, etc. is inversely related to prostate cancer risk, although the mechanism of prevention and the responsible phytochemicals are unknown. Since clinically significant prostate cancer eventually can grow independent of androgen, the association of the growth and tumorigenesis of such prostate cancer cells with sulforaphane (SFN) which is a predominant isothiocyanate in cruciferous vegetables, investigated. These vegetables contain high concentrations of glucosinolate glucoraphanin, which yield sulforaphane when hydrolyzed by the plant enzyme myrosinase. This study showed that exposure of human androgen-independent DU-145 prostate cancer cells to SFN resulted in the inhibition of growth and tumorigenesis, as revealed by a reduction in cell density, DNA synthesis, and clonogenesis. Analyses of the mechanism revealed that SFN mediated cell cycle arrest by modulating the expression and functions of cell cycle regulators. SFN induced signals that inhibited the activity of cyclin-dependent kinase cdk4 with an up-stream induction of cdk inhibitor p21WAF-1/Cip-1, and reduced cyclin D1. The inhibition of cdk kinase activity could be affected with <1 micro M SFN within 24 h. As a result, phosphorylation of Rb proteins, which activates the transition from G1- to S-phase, was significantly decreased and the cell cycle progression retarded. SFN also down-regulated the expression of bcl-2, a suppressor of apoptosis, and activated caspases to execute apoptosis in the prostate cancer cells. The regulators of cell cycle have thus been revealed as targets of sulforaphane for growth arrest and apoptosis induction. The potential of SFN, as an active dietary factor to inhibit initiation and post-initiation of prostate cancer carcinogenesis is discussed.
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PMID:Targeting cell cycle machinery as a molecular mechanism of sulforaphane in prostate cancer prevention. 1465 56

It has become clear in the past decade that most human malignancies, including lung neoplasms, have aberrations in cell cycle control. The tumor suppressor gene retinoblastoma is an important player in the G1/S transition and its function is abnormal in most human neoplasms. Retinoblastoma function is lost as a result of phosphorylation by the cyclin-dependent kinases (CDKs). Thus, modulation of CDKs may have an important use for the therapy and prevention of human neoplasms. Direct CDK modulators are small molecules that target specifically the adenosine triphosphate binding site of CDKs. In contrast, indirect CDK modulators affect CDK function by modulation of upstream pathways required for CDK activation. The first example of a direct small-molecule CDK modulator tested in the clinic, flavopiridol, is a pan-CDK inhibitor that not only promotes cell cycle arrest but also halts transcriptional elongation, promotes apoptosis, induces differentiation, and has antiangiogenic properties. The second example of direct small-molecule CDK modulators tested in clinical trials is UCN-01 (7-hydroxystaurosporine). UCN-01 has interesting preclinical features: it inhibits Ca2+-dependent protein kinase C, promotes apoptosis, arrests cell cycle progression at G1/S, and abrogates checkpoints upon DNA damage. In summary, novel small-molecule CDK modulators are being tested in the clinic with interesting results. Although these small molecules are directed toward a very prevalent cause of carcinogenesis, their role in the clinical armamentarium is still uncertain.
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PMID:Cell cycle modulators for the treatment of lung malignancies. 1466 71

p16(INK4a) (hereafter referred to as p16), a major cyclin-dependent kinase (CDK) inhibitor, is the product of a tumor-suppressor gene that has been found inactivated in different cancer types. In the present study, we sought to investigate the role of p16 in apoptosis induced by ultraviolet light (the most important etiological cause of skin cancer) and cisplatin (an anticancer DNA damaging agent). It is clearly shown that p16-compromised osteosarcoma U2OS cell line and p16-/- mouse embryo fibroblasts are sensitive to UV-induced apoptosis, as compared to their respective isogenic p16-expressing cells (EH1, EH2) and p16 +/+, indicating that p16 protects cells from undergoing apoptosis in response to UV light. Importantly, this reduction in UV-mediated apoptosis was associated with downregulation of the proapoptotic Bax protein, with no effect on Bcl-2 expression, suggesting that this antiapoptotic role of p16 is mediated via the intrinsic-mitochondrial pathway. On the other hand, p16 sensitized cells to cisplatin-mediated apoptosis through Bcl-2 decline. Interestingly, only proliferating but not G1-arrested EH1 cells underwent apoptosis in response to the anticancer drug. These novel findings provide further insight into the role of p16 in carcinogenesis, and has potential implications for future therapy strategies.
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PMID:The tumor suppressor p16(INK4a) gene is a regulator of apoptosis induced by ultraviolet light and cisplatin. 1471 25

p27Kip1 belongs to the family of small polypeptides collectively termed cyclin-dependent kinase inhibitors, which negatively regulate the cell cycle progression. In various human cancers, the reduced p27Kip1 expression correlates well with poor prognosis. Recently, Jab1/CSN5, the fifth component of the COP9 signalosome complex, was found to specifically translocate p27Kip1 from the nucleus to the cytoplasm, and reduce the protein level of p27Kip1 by accelerating its degradation. In this study, we investigated the expression of p27Kip1 and Jab1 in 61 cases with pancreatic ductal adenocarcinoma. The p27Kip1 expression was positive in 41% (25/61) of the tumors. Of the 25 positive tumors, 12 cases had p27Kip1 positive expression mainly in the nucleus of the tumor cells, while 13 cases had p27Kip1 in the cytoplasm as well as in the nucleus. Among a variety of clinicopathological factors, only tumor status was inversely correlated with p27Kip1 expression (p=0.019). The Jab1 expression was detected both in the nucleus and the cytoplasm in almost all pancreatic cancer cells. The intensity of Jab1 expression in tumor cells, especially in the cytoplasm, was much stronger than in normal pancreatic ductal epithelial cells. The patients with positive p27Kip1 expression had significantly better prognosis than ones with negative p27Kip1 expression (p=0.008). Furthermore, 12 patients with exclusively nuclear p27Kip1 expression, but not 13 patients with both nuclear and cytoplasmic p27Kip1 expression, had significantly better prognosis than 36 patients with negative p27Kip1 expression (p=0.009). In multivariate survival analysis, localized p27Kip1 expression was an independent prognostic factor (p=0.016). The results of our study suggested that the mislocalization as well as the downregulation of p27Kip1 had significant prognostic value in pancreatic cancer and that Jab1 might play an important role in carcinogenesis of pancreatic cancer. Cell cycle control targeting p27Kip1 might be a promising future therapeutic modality against pancreatic cancer.
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PMID:Prognostic significance of localized p27Kip1 and potential role of Jab1/CSN5 in pancreatic cancer. 1471 54

Impairment of cell cycle control has serious effects on inflammation, tissue repair, and carcinogenesis. We report here the G1 cell cycle arrest by monochloramine (NH2Cl), a physiological oxidant derived from activated neutrophils, and its mechanism. When Jurkat cells were treated with NH2Cl (70 microM, 10 min) and incubated for 24 h, the S phase population decreased significantly with a slight increase in the hypodiploid cell population. The G0/ G1 phase and G2/M phase populations did not show marked changes. Three hours after NH2Cl treatment, the retinoblastoma protein (pRB) was dephosphorylated especially at Ser780 and Ser795, both of which are important phosphorylation sites for the G1 checkpoint function. The phosphorylation at Ser807/811 showed no apparent change. The expression of cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors showed no apparent change. Moreover, the kinase activity that phosphorylates pRB remained constant even after NH2Cl treatment. The protein phosphatase activity that dephosphorylates pRB showed a marginal increase. Notably, when the recombinant pRB was oxidized by NH2Cl in vitro, the oxidized pRB became difficult to be phosphorylated by kinases, especially at Ser780 and Ser795, but not at Ser807/811. Amino acid analysis of oxidized pRB showed methionine oxidation to methionine sulfoxide. The NH2Cl-treated Jurkat cell proteins also showed a decrease in methionine. These observations suggested that direct pRB oxidation was the major cause of NH2Cl-induced cell cycle arrest. In the presence of 2 mM NH4+, NaOCl (200 microM) or activated neutrophils also induced a G1 cell cycle arrest. As protein methionine oxidation has been reported in inflammation and aging, cell cycle modulation by pRB oxidation may occur in various pathological conditions.
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PMID:Cell cycle arrest by monochloramine through the oxidation of retinoblastoma protein. 1473 95

The steroid hormone 1,25-dihydroxyvitamin D(3), [1,25(OH)(2)D(3), calcitriol], the active metabolite of vitamin D, exerts pleiotropic antitumor effects against several malignancies. However, the clinical use of this hormone is limited by hypercalcemia. 25-Hydroxyvitamin D(3), the prohormone of 1,25(OH)(2)D(3), is hydroxylated to the active hormone by the enzyme 25-hydroxyvitamin-1-alpha-hydroxylase [1 alpha(OH)ase]. 1 alpha(OH)ase is found primarily in the kidney, but also is expressed in the prostate, colon and other tissues. Using immunohistochemistry, we report that 1 alpha(OH)ase is highly expressed in both normal and malignant pancreatic tissue. Expression of this enzyme and enzymatic activity was also detected in four pancreatic tumor cell lines. 25(OH)D(3) inhibited the growth of three of four pancreatic cell lines in a manner that correlated with the level of induction of the cyclin-dependent kinase inhibitors p21 and p27 and with the induction of cell cycle arrest at the G(1)/S checkpoint. The growth of a cell line stably transfected with a mutant Ki-ras allele and of a second cell line with an endogenous Ki-ras activating mutation was also inhibited by 25(OH)D(3), indicating that activating Ki-Ras mutations, which occur in almost 90% of pancreatic adenocarcinomas, do not interfere with the growth-inhibitory effects of 25(OH)D(3). The expression of 1 alpha(OH)ase in normal and malignant pancreatic tissue and the antiproliferative effects of the prohormone in these cells, suggest that 25(OH)D(3) may offer possible therapeutic and chemopreventive options for pancreatic cancer.
Carcinogenesis 2004 Jun
PMID:Pancreatic cancer cells express 25-hydroxyvitamin D-1 alpha-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3. 1474 20

The increased expression of cyclooxygenase (COX)-2 significantly enhances carcinogenesis and inflammatory reactions, and its regulation may be a reasonable target for cancer chemoprevention. We demonstrated previously that deguelin inhibits proliferation of premalignant human bronchial epithelial (HBE) cells, such as 1799 cells and squamous HBE cells, by regulating phosphatidylinositol-3-kinase Akt activity, which is involved in COX-2 expression. We sought to determine the effect of deguelin on COX-2 expression in squamous HBE cells. Deguelin strongly inhibited COX-2 expression in squamous HBE cells, without affecting the COX-1 protein level. Deguelin inhibited proliferation of a variety of non-small cell lung carcinoma (NSCLC) cell lines through apoptosis and induced Bax expression in the H322 NSCLC and squamous HBE cells. Deguelin treatment did not affect Bcl-2 protein levels but increased expression levels of the proapoptotic protein p53 and the cyclin-dependent kinase inhibitors p21 and p27 in the squamous HBE cells. The sensitivity of the squamous HBE and NSCLC cells to deguelin and the inhibitory effects of deguelin on COX-2 expression in the squamous HBE cells indicate that regulation of COX-2 expression is involved in the chemopreventive action of deguelin in lung cancer.
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PMID:Deguelin-induced inhibition of cyclooxygenase-2 expression in human bronchial epithelial cells. 1487 87

Mitogenic growth factor- and integrin-dependent signaling pathways cooperate to control the proliferation of nontransformed cells. As integral mediators of these networks, the Rho family of GTPases play a pivotal role in G1 cell cycle progression, primarily through regulation of cyclin D1 expression, as well as the levels of the cyclin-dependent kinase inhibitors p21cip1 and p27kip1. Such dual control of both the critical positive and negative regulators of G1 progression make the Rho GTPases prime candidates to target the autonomous proliferation which typifies cancer cells. Cyclin D1 has been identified as an important oncogene and the cdk inhibitors as tumor suppressors in human breast carcinogenesis. Evidence pointing to the potential role of Rho-dependent pathways and their interaction with oncogenic Ras in contributing to such cell cycle abnormalities that characterize human breast cancer is also presented.
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PMID:Rho GTPases as key transducers of proliferative signals in g1 cell cycle regulation. 1499 52

In the present study, we investigated the in vitro effect of saucernetin-7, which is a dineolignan isolated from Saururus chinensis, on the proliferation, cell cycle-regulation and differentiation of HL-60 human promyelocytic leukemia cells. Saucernetin-7 potently inhibited the proliferation of HL-60 cells in both a dose- and time-dependent manner with an IC50, approximately 5 microM. DNA flow-cytometry indicated that saucernetin-7 markedly induced a G1 phase arrest of HL-60 cells. Among the G1 phase cell cycle-related proteins, the levels of cyclin-dependent kinase (CDK)6 and cyclin D1 were reduced by saucernetin-7, whereas the steady-state levels of CDK2, CDK4, cyclin D2, cyclin D3 and cyclin E were unaffected. The protein and mRNA levels of a CDK inhibitor p21CIP1/WAF1, but not p27KIP1, were markedly increased by saucernetin-7 and p21CIP1/WAF1 induction is likely to occur at the transcriptional level because actinomycin D blocked this induction. In addition, saucernetin-7 markedly enhanced the binding of p21CIP1/WAF1 with CDK2 and CDK6, resulting in the reduced activity of both kinases and the hypophosphorylation of Rb protein. We furthermore suggest that saucernetin-7 is a potent inducer of the differentiation of HL-60 cells, based on observations such as a reduction of the nitroblue tetrazolium level, an increase in the esterase activities and phagocytic activity, morphology changes, and the expression of CD14 and CD66b surface antigens. In conclusion, the onset of saucernetin-7-induced the G0/G1 arrest of HL-60 cells prior to the differentiation is linked to a sharp up-regulation of the p21CIP1/WAF1 level and a decrease in the CDK2 and CDK6 activities. This is the first report demonstrating that saucernetin-7 potently inhibits the proliferation of human promyelocytic HL-60 cells via the G1 phase cell cycle arrest and differentiation induction.
Carcinogenesis 2004 Aug
PMID:Saucernetin-7 isolated from Saururus chinensis inhibits proliferation of human promyelocytic HL-60 leukemia cells via G0/G1 phase arrest and induction of differentiation. 1503 3

Bladder cancer is the fourth and eighth most common cancer in men and women in the USA, respectively. Flavonoid phytochemicals are being studied for both prevention and therapy of various human malignancies including bladder cancer. One such naturally occurring flavonoid is silibinin isolated from milk thistle. Here, we assessed the effect of silibinin on human bladder transitional cell carcinoma (TCC) cell growth, cell cycle modulation and apoptosis induction, and associated molecular alterations, employing two different cell lines representing high-grade invasive tumor (TCC-SUP) and high-grade TCC (T-24) human bladder cancer. Silibinin treatment of these cells resulted in a significant dose- and time-dependent growth inhibition together with a G(1) arrest only at lower doses in TCC-SUP cells but at both lower and higher doses in T-24 cells; higher silibinin dose showed a G(2)/M arrest in TCC-SUP cells. In other studies, silibinin treatment strongly induced the expression of Cip1/p21 and Kip1/p27, but resulted in a decrease in cyclin-dependent kinases (CDKs) and cyclins involved in G(1) progression. Silibinin treatment also showed an increased interaction between cyclin-dependent kinase inhibitors (CDKIs)-CDKs and a decreased CDK kinase activity. Further, the G(2)/M arrest by silibinin in TCC-SUP cells was associated with a decrease in pCdc25c (Ser216), Cdc25c, pCdc2 (Tyr15), Cdc2 and cyclin B1 protein levels. In additional studies, silibinin showed a dose- and a time-dependent apoptotic death only in TCC-SUP cells that was associated with cleaved forms of caspase 3 and poly(ADP-ribose) polymerase. Together, these results suggest that silibinin modulates CDKI-CDK-cyclin cascade and activates caspase 3 causing growth inhibition and apoptotic death of human TCC cells, providing a strong rationale for future studies evaluating preventive and/or intervention strategies for silibinin in bladder cancer pre-clinical models.
Carcinogenesis 2004 Sep
PMID:Silibinin causes cell cycle arrest and apoptosis in human bladder transitional cell carcinoma cells by regulating CDKI-CDK-cyclin cascade, and caspase 3 and PARP cleavages. 1511 15


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