5-Aza-2<b>′</b>-deoxycytidine Restores Proapoptotic Function of p53 in Cancer Cells Resistant to p53-induced Apoptosis

Yagi, Shutaro; Oda-Sato, Eri; Uehara, Ikuno; Asano, Yumi; Nakajima, Wataru; Takeshita, Toshiyuki; Tanaka, Nobuyuki

doi:10.1080/07357900701840212

Cited by 8 publications

(6 citation statements)

References 42 publications

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“…In this work we have highlighted the marked ability of CP to inhibit cell viability of colon cancer cell, mostly characterized by the predominance of antiapoptotic factors or defects in apoptosis effectors. In particular, among all cell lines, CP was highly effective even against SW480 and DLD1 colon cancer cells, in which mutation of p53 gene or high expression of mitochondrial COX‐2, respectively, conferred resistance to apoptosis [43, 44]. CP ability to trigger an apoptosis‐independent stress response represents an interesting property that may expand its spectrum of action towards aggressive cancers characterized by apoptosis resistance.…”

Section: Discussionmentioning

confidence: 99%

A novel copper complex induces paraptosis in colon cancer cells via the activation of ER stress signalling

Gandin

Pellei

Tisato³

et al. 2011

J Cellular Molecular Medi

133

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Platinum anticancer drugs have been used for three decades despite their serious side effects and the emerging of resistance phenomena. Recently, a phosphine copper(I) complex, [Cu(thp)4][PF6] (CP), gained special attention because of its strong antiproliferative effects. CP killed human colon cancer cells more efficiently than cisplatin and oxaliplatin and it overcame platinum drug resistance. CP preferentially reduced cancer cell viability whereas non-tumour cells were poorly affected. Colon cancer cells died via a programmed cell death whose transduction pathways were characterized by the absence of hallmarks of apoptosis. The inhibition of 26S proteasome activities induced by CP caused intracellular accumulation of polyubiquitinated proteins and the functional suppression of the ubiquitin–proteasome pathway thus triggering endoplasmic reticulum stress. These data, providing a mechanistic characterization of CP-induced cancer cell death, shed light on the signaling pathways involved in paraptosis thus offering a new tool to overcome apoptosis-resistance in colon cancer cells.

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Section: Discussionmentioning

confidence: 99%

A novel copper complex induces paraptosis in colon cancer cells via the activation of ER stress signalling

Gandin

Pellei

Tisato³

et al. 2011

J Cellular Molecular Medi

133

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“…Expression of p53AIP1 is primarily regulated by p53. Activation of p53 by a number of factors, such as DNA damage, induces the transcription of p53AIP1 (7)(8)(9)(10). In contrast to the p53-mediated regulation of p21 and MDM2, which involves the phosphorylation of Ser-15 of p53 (11,12), induction of p53aip1 mrna and its apoptotic function was uniquely associated with the phosphorylation of Ser-46 of p53 (4).…”

Section: Introductionmentioning

confidence: 99%

Adenovirus Ad-p53AIP1-mediated gene therapy and its regulation of p53-MDM2 interactions

Jiang¹,

Chen²,

Jia³

et al. 2010

Experimental and Therapeutic Medicine

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We generated replication-defective adenovirus Ad-p53AIP1 and studied its anti-tumor efficacy both in vitro and in vivo. We demonstrated that Ad-p53AIP1 infection elicited high levels of p53AIP1 expression in cancer cells. We also found that Ad-p53AIP1 expression induced marked apoptosis and cell cycle arrest in HepG2 cells. Moreover, Ad-p53AIP1 infection significantly inhibited the tumorigenesis of 4T1 mouse mammary cancer cells in vivo. In particular, we discovered that p53AIP1 overexpression up-regulated the protein levels of p53 in HepG2 cells, which was accompanied by down-regulation of MDM2 mRNA and protein, suggesting an interaction between MDM2 and p53 in p53AIP1-induced apoptosis and cell cycle arrest. Our data demonstrated the feasibility of Ad-p53AIP1-mediated cancer gene therapy. p53AIP1-induced up-regulation of p53 protein through MDM2 suggests that p53AIP1 gene therapy may be more advantageous in tumors expressing high levels of oncoprotein MDM2 or having a mutation in MDM2 inhibitor p16INK4.

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“…NOXA is a p53-target gene and NOXA regulates p53-dependent apoptosis [ 56 , 66 ], which is an important tumor suppressor mechanism of p53 [ 67 ]. We previously found that the induction of NOXA by p53 was suppressed in some colon cancer cells that show resistance to apoptosis by p53 overexpression and that lack NOXA inducibility by p53 was restored by 5-azacytidine [ 68 ]. These findings indicated the possibility that the expression of transcription factor(s) that induce NOXA is suppressed by methylation.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Priming with Decitabine Augments the Therapeutic Effect of Cisplatin on Triple-Negative Breast Cancer Cells through Induction of Proapoptotic Factor NOXA

Nakajima

Miyazaki

Sakaguchi

et al. 2022

Cancers

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Epigenetic alterations caused by aberrant DNA methylation have a crucial role in cancer development, and the DNA-demethylating agent decitabine, is used to treat hematopoietic malignancy. Triple-negative breast cancers (TNBCs) have shown sensitivity to decitabine; however, the underlying mechanism of its anticancer effect and its effectiveness in treating TNBCs are not fully understood. We analyzed the effects of decitabine on nine TNBC cell lines and examined genes associated with its cytotoxic effects. According to the effect of decitabine, we classified the cell lines into cell death (D)-type, growth inhibition (G)-type, and resistant (R)-type. In D-type cells, decitabine induced the expression of apoptotic regulators and, among them, NOXA was functionally involved in decitabine-induced apoptosis. In G-type cells, induction of the cyclin-dependent kinase inhibitor, p21, and cell cycle arrest were observed. Furthermore, decitabine enhanced the cytotoxic effect of cisplatin mediated by NOXA in D-type and G-type cells. In contrast, the sensitivity to cisplatin was high in R-type cells, and no enhancing effect by decitabine was observed. These results indicate that decitabine enhances the proapoptotic effect of cisplatin on TNBC cell lines that are less sensitive to cisplatin, indicating the potential for combination therapy in TNBC.

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5-Aza-2′-deoxycytidine Restores Proapoptotic Function of p53 in Cancer Cells Resistant to p53-induced Apoptosis

Cited by 8 publications

References 42 publications

A novel copper complex induces paraptosis in colon cancer cells via the activation of ER stress signalling

A novel copper complex induces paraptosis in colon cancer cells via the activation of ER stress signalling

Adenovirus Ad-p53AIP1-mediated gene therapy and its regulation of p53-MDM2 interactions

Epigenetic Priming with Decitabine Augments the Therapeutic Effect of Cisplatin on Triple-Negative Breast Cancer Cells through Induction of Proapoptotic Factor NOXA

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