Methylation-induced silencing of ASC and the effect of expressed ASC on p53-mediated chemosensitivity in colorectal cancer

Ohtsuka, Takao; Xf, Liu; Koga, Yasuo; Kitajima, Yoshihiko; Nakafusa, Yuji; Ha, Chul‐Won; Sw, Lee; Miyazaki, Kohji

doi:10.1038/sj.onc.1209204

Cited by 27 publications

(17 citation statements)

References 20 publications

(22 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Activated p53 promotes the transcription of p21/Waf1, which causes cell cycle arrest at the G 1 phase by inhibiting CDKs, and p53R2, bearing DNA repair [22]. Caco-2 cells express p53 [23], but otherwise CW2 cells do not express p53 [24]. This indicates that p53 is not responsible for irinotecan-induced cell cycle arrest both in Caco-2 and CW2 cells.…”

Section: Discussionmentioning

confidence: 99%

Irinotecan Induces Cell Cycle Arrest, but Not Apoptosis or Necrosis, in Caco-2 and CW2 Colorectal Cancer Cell Lines

Kaku¹,

Tsuchiya²,

Kanno³

et al. 2015

Pharmacology

View full text Add to dashboard Cite

Irinotecan, a topoisomerase I inhibitor, is clinically used as an anticancer drug. The present study investigated the anticancer effect of irinotecan on p53-negative Caco-2 and p53-positive CW2 human colorectal cancer cell lines. Cell viability for both Caco-2 and CW2 cells was little affected by treatment with irinotecan at concentrations ranging from 0.3 to 30 μmol/l for 24-48 h. Irinotecan did not increase the number of TUNEL-positive cells and did not affect the population of propidium iodide (PI)-positive and annexin V-negative cells, corresponding to primary necrosis, or that of PI-positive and annexin-positive cells, corresponding to late apoptosis/secondary necrosis, in either of the two cell lines. In the cell cycle analysis, irinotecan significantly increased the proportions at the S and G₂/M phases of cell cycling in parallel with a decreased population at the G₁ phase in both cell lines. Irinotecan significantly inhibited tumor growth in mice inoculated with CW2 cells. Taken together, these results indicate that irinotecan induces cell cycle arrest, but not apoptosis or necrosis, both in Caco-2 and CW2 cells, leading to suppression of cell proliferation.

show abstract

Section: Discussionmentioning

confidence: 99%

Irinotecan Induces Cell Cycle Arrest, but Not Apoptosis or Necrosis, in Caco-2 and CW2 Colorectal Cancer Cell Lines

Kaku¹,

Tsuchiya²,

Kanno³

et al. 2015

Pharmacology

View full text Add to dashboard Cite

show abstract

“…3). ASC has 2 protein adaptor domains, and therefore has the potential to bind to various types of molecules, regulating cellular death in response to various death stimuli (9)(10)(11)(12). Since there have been no reports describing the relationship between ASC and hypoxia, subsequent study should identify the hypoxia-inducible genes which collaborate with ASC under hypoxia.…”

Section: Discussionmentioning

confidence: 99%

“…We previously demonstrated that ASC is a target gene of p53 and regulates the p53-Bax mitochondrial apoptotic pathway induced by many chemotherapeutic drugs (10,11). As well, we showed that ASC can regulate the p53-independent apoptotic pathway by such agents as tumor necrosis factor (TNF)-α or indomethacin (10).…”

Section: Introductionmentioning

confidence: 99%

Role of ASC in hypoxia-mediated cell death in pancreatic cancer

et al. 2008

View full text Add to dashboard Cite

Abstract. ASC, an apoptosis-associated speck-like protein, can regulate apoptosis in response to various types of cell death stimuli. In this study, we investigated the role of ASC in hypoxia-mediated cell death in pancreatic cancer. ASC was inducible under a 1% O 2 hypoxic condition in pancreatic cancer cells, which was HIF1α-dependent but p53-independent. Two representative chemotherapeutic agents for pancreatic cancer, 5-fluorouracil and gemcitabine, promoted cell death in a p53-dependent manner; however, 1% hypoxia caused chemoresistance to these drugs. Western blot analysis of this condition showed that expression of Bax, a pro-apoptotic gene, decreased, while the anti-apoptotic genes IAP-2 and survivin increased. These results suggest that, although hypoxia induces both pro-apoptotic and anti-apoptotic genes, the total balance seems to be anti-apoptotic dominant, which might explain chemoresistance in pancreatic cancer. To overcome this antiapoptotic dominant condition, we infected adenovirusexpressing ASC into pancreatic cancer cells. The expressed ASC induced cell death even under 20% normoxia, and was enhanced by hypoxia. Our data demonstrate the possible mechanism of chemoresistance under hypoxia in pancreatic cancer cells, thereby suggesting the potential use of ASC as a new treatment strategy for pancreatic cancer.

show abstract

“…Gene methylation in cancer cells leads to epigenetic gene silencing and plays an important role in carcinogenesis, cancer progression and drug resistance (5)(6)(7)(8)(9). A methylation analysis in cancer tissues has been widely examined by the MSP method.…”

Section: Discussionmentioning

confidence: 99%

“…Thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and ortate phosphoribosyltransferase (OPRT), which are critical enzymes in the metabolism of 5-fluorouracil (5-FU) could be important factors determining chemosensitivity to 5-FU or the modified agent, S-1 (2-4). Besides, aberrant promoter methylation of tumor suppressor genes, DNA repair genes, and cell cycle checkpoint genes are frequently found in human primary CRC and show a significant correlation with carcinogenesis, tumor progression and chemosensitivity (5)(6)(7)(8)(9). There is a relationship between aberrant gene methylation and chemosensitivity to anticancer drugs, for example CHFR and microtubule inhibitors in gastric cancer tissues and cell lines, p16 and 5-FU-based therapy in gastric cancer tissues, hMLH1 and 5-FU-based therapy in colorectal cancer tissues (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

CpG island methylation of BNIP3 predicts resistance against S-1/CPT-11 combined therapy in colorectal cancer patients

Hiraki

Kitajima²,

Nakafusa³

et al. 2009

Oncol Rep

View full text Add to dashboard Cite

Abstract. Aberrant gene methylation is frequently observed in various cancers and plays an important role in carcinogenesis, cancer progression and drug responsiveness. The aim of this study is to identify colorectal cancer specific gene methylation determining chemosensitivity to S-1/CPT-11 therapy. The gene methylation of CHFR, p16, RUNX3, Ecadherin, MGMT, hMLH1, ABCG2, UGT1A1 and BNIP3 genes were analyzed in 27 colorectal cancer tissues by quantitative methylation-specific PCR (q-MSP). All 27 patients were postoperatively treated by S-1/CPT-11 therapy targeting the metastatic lesion and the recurrent tumor. Thereafter, the patients were divided into a responder group (RG) or a non-responder group (NRG) according to the effect of the chemotherapy. There were 13 cases of RG (48.1%) and 14 cases of NRG (51.9%). The methylation level in CHFR, RUNX3 and BNIP3 was significantly higher in cancer lesions in comparison to the non-cancerous lesion. Only methylation of the BNIP3 gene was significantly higher in primary cancer tissue of the NRG than the RG. The correlation between the BNIP3 methylation status and time to progression (TTP) suggested that the low methylation group (n=16) resulted in a significantly longer TTP, in comparison to the high methylation group (n=11; P=0.004). The methylation level of BNIP3 showed a significant inverse correlation with the mRNA expression suggesting the DNA methylation suppressed BNIP3 expression (r=-0.466, P=0.021). In conclusion, BNIP3 gene methylation is a possible marker predicting a poor response to the S-1/CPT-11 combined therapy in colorectal cancer.

show abstract

Methylation-induced silencing of ASC and the effect of expressed ASC on p53-mediated chemosensitivity in colorectal cancer

Cited by 27 publications

References 20 publications

Irinotecan Induces Cell Cycle Arrest, but Not Apoptosis or Necrosis, in Caco-2 and CW2 Colorectal Cancer Cell Lines

Irinotecan Induces Cell Cycle Arrest, but Not Apoptosis or Necrosis, in Caco-2 and CW2 Colorectal Cancer Cell Lines

Role of ASC in hypoxia-mediated cell death in pancreatic cancer

CpG island methylation of BNIP3 predicts resistance against S-1/CPT-11 combined therapy in colorectal cancer patients

Contact Info

Product

Resources

About