p16<sup>INK4</sup> Expression Is Associated with the Increased Sensitivity of Human Non‐small Cell Lung Cancer Cells to DNA Topoisomerase I Inhibitors

Fukuoka, Kazuya; Adachi, Jun-ichi; Nishio, Kazuto; Arioka, Hitoshi; Kurokawa, Hirokazu; Fukumoto, Hisao; Ishida, Tomoyuki; Nomoto, Tomoko; Yokote, Hideyuki; Tomonari, Akira; Narita, Nobuhiro; Yokota, Jun; Saijo, Nagahiro

doi:10.1111/j.1349-7006.1997.tb00322.x

Cited by 21 publications

(24 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fukuoka et al 7 reported that transfection of p16/CDKN2 gene into human nonsmall lung cancer cells resulted in increased sensitivity to topoisomerase inhibitors, doxorubicin, mitomycin C and 5-fluorouracil. Sading et al 8 suggested that simultaneously transfected wild-type p16/CDKN2 gene and wild-type TP53 gene induce apoptotic tumor cell death cooperatively in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…4 The putative tumor-suppresser genes, p16/CDKN2 and p15/ MTS2, are known to be inactivated by deletion, mutation and hypermethylation in a variety of human tumors. 5,6 Since several studies indicate controversial impacts of the gene inactivation on in vitro sensitivity to chemotherapeutic agents including cisplatin, [7][8][9][10] its contribution to the drug-resistance phenotype in cancer patients is not well understood.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Inactivation of p16/CDKN2 and p15/MTS2 is associated with prognosis and response to chemotherapy in ovarian cancer

Kudoh¹,

Ichikawa

Yoshida

et al. 2002

Intl Journal of Cancer

View full text Add to dashboard Cite

To define the involvement of p16/CDKN2 and p15/MTS2 tumor-suppressor genes for response to chemotherapy in primary epithelial ovarian cancer, we analyzed alterations of the gene in 45 patients who were treated with primary cytoreductive surgery followed by 6 courses of cis-diamminedichloroplatinum (II) (cisplatin)-based combination chemotherapy. Homozygous deletion of p16/CDKN2 and p15/MTS2 genes was found in 8 (18%) and 15 (33%) cases, respectively. Response to the chemotherapy was confirmed by finding at second surgery after the chemotherapy in 26 patients, resulting in 17 responders and 9 nonresponders. The abundance of gene deletion in nonresponders (56%) was significantly higher (p ‫؍‬ 0.0463) when compared to that in responders (18%). Moreover, the deletion of genes was a significant poor prognostic factor (p ‫؍‬ 0.0441) in advanced ovarian cancer. These results suggest that deletion of p16/CDKN2 and/or p15/MTS2 is a potential indicator for poor chemotherapy response and adverse prognosis in ovarian cancer patients. © 2002 Wiley-Liss, Inc. Key words: p16/CDKN2; p15/MTS2; chemotherapy; ovarian cancerOvarian cancer is the leading cause of death from gynecologic malignancy. Cisplatin-based chemotherapy has played an important role in the treatment of ovarian cancer and has resulted in a substantially improved response rate of approximately 60%. 1,2 However, the overall survival of the advanced cancer has remained unimproved at around 20% because considerable numbers of patients harbor resistant or refractory tumor to chemotherapy. 3 The mechanism of cisplatin resistance is estimated to be multifactorial and it remains unclear how genetic events are associated with the resistance in ovarian cancer. 4 The putative tumor-suppresser genes, p16/CDKN2 and p15/ MTS2, are known to be inactivated by deletion, mutation and hypermethylation in a variety of human tumors. 5,6 Since several studies indicate controversial impacts of the gene inactivation on in vitro sensitivity to chemotherapeutic agents including cisplatin, 7-10 its contribution to the drug-resistance phenotype in cancer patients is not well understood.To clarify the involvement of p16/CDKN2 and p15/MTS2 inactivation with response to cisplatin-based chemotherapy, we examined the alteration of the genes in 45 primary ovarian cancers using the PCR method and analyzed the relationship between gene inactivation and sensitivity to the chemotherapy retrospectively. MATERIAL AND METHODS Patients, chemotherapy and response evaluationForty-five primary epithelial ovarian cancer patients who were treated at National Defense Medical College hospital (Saitama, Japan) during 1988 -1996 were enrolled in our study. Samples analyzed were obtained from the patients at the first surgery with an appropriate informed consent. Multiple specimens with characteristic appearance of cancer (i.e., papillary growth) were removed from the bulk tissue and the adjacent portion was examined microscopically to eliminate samples with rich interstitial tissue to minimize normal tissue cont...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inactivation of p16/CDKN2 and p15/MTS2 is associated with prognosis and response to chemotherapy in ovarian cancer

Kudoh¹,

Ichikawa

Yoshida

et al. 2002

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…The log of the normalized p21 mRNA levels was plotted against time following actinomycin D treatment. All the values are expressed relative to time 0 h, which was arbitrarily assigned the value of 1. this question (42). Two novel inhibitors of DNA MeTase that inhibit DNA MeTase by different mechanisms were used to increase the confidence that the effects observed were a consequence of DNA MeTase inhibition.…”

Section: Discussionmentioning

confidence: 99%

DNA Methyltransferase Inhibition Induces the Transcription of the Tumor Suppressor p21

Milutinovic

Knox

Szyf

2000

Journal of Biological Chemistry

113

View full text Add to dashboard Cite

Previous lines of evidence have shown that inhibition of DNA methyltransferase (MeTase) can arrest tumor cell growth; however, the mechanisms involved were not clear. In this manuscript we show that out of 16 known tumor suppressors and cell cycle regulators, the cyclin-dependent kinase inhibitor p21 is the only tumor suppressor induced in the human lung cancer cell line, A549, following inhibition of DNA MeTase by a novel DNA MeTase antagonist or antisense oligonucleotides. The rapid induction of p21 expression points to a mechanism that does not involve demethylation of p21 promoter. Consistent with this hypothesis, we show that part of the CpG island upstream of the endogenous p21 gene is unmethylated and that the expression of unmethylated p21 promoter luciferase reporter constructs is induced following inhibition of DNA MeTase. These results are consistent with the hypothesis that the level of DNA MeTase in a cell can control the expression of a nodal tumor suppressor by a mechanism that does not involve DNA methylation.DNA methylation of cytosine residues located at the dinucleotide sequence CpG can suppress expression of genes either by directly interfering with the binding of transcription factors (1) or by attracting methylated-DNA binding proteins such as MeCP2 (2-4). To ascertain that the epigenetic information encoded in the methylation pattern is faithfully maintained, the expression of the maintenance DNA MeTase 1 enzyme DNMT1, which catalyzes the transfer of a methyl group from S-adenosyl-methionine to the 5Ј position on cytosines residing at the dinucleotide CpG (5), is tightly coordinated with DNA replication (6) and the state of growth of the cell (7). Different protooncogenic pathways can up-regulate dnmt1 expression (8), and high levels of dnmt1 mRNA have been observed in many cancer cells (9, 10). It has been proposed that increased DNA MeTase levels are a downstream component of oncogenic programs (11) and that they play a causal role in cellular transformation (12, 13). This hypothesis has been supported by the observation that a reduction in DNA MeTase levels by either 5-aza-deoxycytidine (13, 14), DNA MeTase antisense mRNA or antisense oligonucleotides can reverse tumor growth in vivo and in vitro (13-15).The mechanisms responsible for cellular transformation by DNMT1 and the reversal of transformation by DNA MeTase inhibition are unknown. One attractive hypothesis is that high levels of DNA MeTase lead to ectopic methylation and inactivation of tumor suppressor genes such as p16 (16). Similarly, the inhibition of DNA MeTase could result in demethylation and lead to activation of p16 (17, 18). However, because both the increase in DNA MeTase levels and its inhibition by pharmacological inhibitors are global processes, it is difficult to understand how they could predictably result in a discrete change of the methylation state of specific sites. A more likely explanation is that ectopic methylation of tumor suppressors in tumor cells is a slow and stochastic process, but the aberrant meth...

show abstract

“…A549 cells have been reported to have a homozygous deletion of CDKN2a (36). Therefore, we hypothesized that p21…”

Section: Dose-dependent Inhibition Of Cell Proliferation By 5-aza-mentioning

confidence: 99%

5-Aza-2′-deoxycytidine Activates the p53/p21Waf1/Cip1 Pathway to Inhibit Cell Proliferation

Zhu

Hileman

et al. 2004

Journal of Biological Chemistry

143

View full text Add to dashboard Cite

In addition to its demethylating function, 5-aza-2-deoxycytidine (5-aza-CdR) also plays an important role in inducing cell cycle arrest, differentiation, and cell death. However, the mechanism by which 5-aza-CdR induces antineoplastic activity is not clear. In this study, we found that 5-aza-CdR at limited concentrations (0.01-5 M) induces inhibition of cell proliferation as well as increased p53/p21Waf1/Cip1 expression in A549 cells (wild-type p53) but not in H1299 (p53-null) and H719 cells (p53 mutant). The p53-dependent p21 As demethylating agents, 5-aza-cytidine and 5-aza-2Ј-deoxycytidine (5-aza-CdR) 1 have been extensively used for epigenetic research (1-4). Both demethylating agents are incorporated into DNA where they bind DNA methyltransferase (DNMT) in an irreversible, covalent manner, thus sequestering the enzyme and preventing maintenance of the methylation state (5-7). Consequently, silenced genes induced by hypermethylation are re-expressed after treatment with these demethylating agents.Originally, 5-aza-cytidine and 5-aza-CdR were developed as anticancer agents (5, 8) and have been shown to have significant cytotoxic and antineoplastic activities in many experimental tumors (9 -12). 5-Aza-CdR is reported to be noncarcinogenic and incorporates into DNA but not RNA or protein (13,14). 5-Aza-CdR has been found empirically to have more potent therapeutic effects than 5-aza-cytidine in cell culture and animal models of human cancers. However, 5-aza-CdR-induced cytotoxicity may not be linked to its demethylating function (3,(15)(16)(17). In addition, the therapeutic effects of 5-aza-CdR in the treatment of different human cancer cells are conflicting. 5-Aza-CdR appears to be beneficial in the treatment of human leukemias (9,18,19), myelodysplastic syndromes (20, 21), and hemoglobinopathies (22, 23). On the other hand, there has been less positive experience in the effectiveness of 5-aza-CdR for the treatment of human solid tumors (10, 24). Therefore, it is possible that one or more critical factors may be involved in regulating the cellular response to 5-aza-CdR treatment that vary in different cell types.p53 is a very important tumor suppressor gene and is reported to be abnormal in more than 50% of human cancers (25). Chemotherapeutic agents frequently act through the mechanism of DNA damage, and p53 plays an important role in the induction of cell cycle arrest and apoptosis in response to DNA damage (26). 5-Aza-CdR has also shown anticancer activity that may be related to its ability to induce DNA damage (15,27). Based on the scenario mentioned above, it is hypothesized that 5-aza-CdR may induce DNA damage, thereby activating p53, which in turn increases p21Waf1/Cip1 expression, leading to the inhibition of cell proliferation.To confirm the role of p53 in the 5-aza-CdR-induced inhibition of cell proliferation, human lung cancer cells with different p53 status were selected as the targets for this study. As an important downstream target of p53 activation, p21Waf1/Cip1 plays a critical role in inhibit...

show abstract

p16^INK4 Expression Is Associated with the Increased Sensitivity of Human Non‐small Cell Lung Cancer Cells to DNA Topoisomerase I Inhibitors

Cited by 21 publications

References 31 publications

Inactivation of p16/CDKN2 and p15/MTS2 is associated with prognosis and response to chemotherapy in ovarian cancer

Inactivation of p16/CDKN2 and p15/MTS2 is associated with prognosis and response to chemotherapy in ovarian cancer

DNA Methyltransferase Inhibition Induces the Transcription of the Tumor Suppressor p21

5-Aza-2′-deoxycytidine Activates the p53/p21Waf1/Cip1 Pathway to Inhibit Cell Proliferation

Contact Info

Product

Resources

About

p16INK4 Expression Is Associated with the Increased Sensitivity of Human Non‐small Cell Lung Cancer Cells to DNA Topoisomerase I Inhibitors

Cited by 21 publications

References 31 publications

Inactivation of p16/CDKN2 and p15/MTS2 is associated with prognosis and response to chemotherapy in ovarian cancer

Inactivation of p16/CDKN2 and p15/MTS2 is associated with prognosis and response to chemotherapy in ovarian cancer

DNA Methyltransferase Inhibition Induces the Transcription of the Tumor Suppressor p21

5-Aza-2′-deoxycytidine Activates the p53/p21Waf1/Cip1 Pathway to Inhibit Cell Proliferation

Contact Info

Product

Resources

About

p16^INK4 Expression Is Associated with the Increased Sensitivity of Human Non‐small Cell Lung Cancer Cells to DNA Topoisomerase I Inhibitors