5-aza-2′-deoxycytidine upregulates caspase-9 expression cooperating with p53-induced apoptosis in human lung cancer cells

Gomyo, Yoshihito; Sasaki, Ji Ichiro; Branch, Cynthia D.; Roth, Jack A.; Mukhopadhyay, Tapas

doi:10.1038/sj.onc.1207381

Cited by 68 publications

(59 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To confirm this and the pro-apoptotic effect of SFN, we examined caspase 3 and caspase 9 activity, which are related to apoptosis induced by SFN. 24,25 As shown in Figure 1E and F, caspase activities were inhibited, except for caspase 3 in TSA group. Then, we selected the SFN10 group and analyzed HDAC activity in different treatments.…”

Section: Resultsmentioning

confidence: 76%

“…The reduction detected after 2 d of treatment may be due to apoptotic response to 5-aza-dC and high dose of SFN. 6,24,25 We then aimed to investigate the effects of 5-azadC on the DNA methylation status, and how the alteration of promoter region methylation affected gene expression. DNMT1 remarkably downregulated in the 5-aza-dC group (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…These results are in line with previous studies that report that SFN significantly decreased the expression of DNMT1 in response to SFN in breast cancer cells 34 and prostate cancer cells. 35 Gomyo et al 24 and Singh et al 25 reported that 5-aza-dC and SFN-induced apoptosis is associated with activation of caspase-3 and caspase-9. SFN dramatically reduced the activity of caspase-3 in the cortex and hippocampus after hypoxia-ischemia insult 36 and was able to counteract rat skeletal muscle damage induced by acute exercise.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Sulforaphane causes a major epigenetic repression of myostatin in porcine satellite cells

et al. 2012

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Sulforaphane causes a major epigenetic repression of myostatin in porcine satellite cells

et al. 2012

View full text Add to dashboard Cite

“…Both epigenetic and transcriptional factor-mediated regulation of Apaf-1 and PC-9 expression levels plays an important role in predisposition of cells to activate the apoptosome apparatus (4)(5)(6)(7)(8). However, the processes of apoptosome assembly and functioning in cancer cells are under a variety of negative and positive modes of post-translational regulation (9,10).…”

Section: Introductionmentioning

confidence: 99%

Down-regulated expression of apoptosis-associated genes APIP and UACA in non-small cell lung carcinoma

et al. 2012

View full text Add to dashboard Cite

Abstract. The Apaf-1 interacting protein (APIP) and the uveal autoantigen with coiled coil domains and ankyrin repeats (UACA) belong to endogenous regulators of the apoptosome apparatus, but their role in tumourigenesis and progression of non-small cell lung carcinoma (NSCLC) is not known. Previous studies demonstrated that APIP inhibits the apoptosome-mediated procaspase-9 activation while UACA induces translocation of Apaf-1 from the cytoplasm into the nucleus. Here, we report for the first time that the expression of APIP and UACA genes is down-regulated on the level of both mRNA and protein in NSCLC cells and tumours. In particular, the expression of APIP protein was strikingly decreased and the expression of UACA mRNA and protein was frequently down-regulated in NSCLC tumours of different histopathological types. Moreover, stage IA NSCLC tumours showed significantly lower expression of UACA mRNA compared to higher stage tumours. The weak increase of both APIP and UACA mRNA levels in the 5-aza-2'-deoxycytidine-treated NSCLC cells indicates that mechanisms other than DNA methylation are involved in the regulation of APIP and UACA gene expression in these cancer cells. Taken together, the down-regulation of APIP and UACA expression suggests that the threshold to activate the apoptosome apparatus may be decreased in NSCLC cells due to the lack of APIP-mediated suppression and UACA-assisted Apaf-1 nuclear entry. Moreover, the loss of UACA-assisted Apaf-1 nuclear translocation may underlie the failure of DNA damage checkpoint activation in NSCLC cells leading to their genomic instability. IntroductionThe apoptosome apparatus is a stress-induced cell death signalling platform that is assembled in the cytosol via the cytochrome-c (cyt-c)-and (d)ATP-mediated formation of an Apaf-1 heptameric complex, which recruits and activates the apoptosis initiator procaspase-9 (PC-9) (1-3). Both epigenetic and transcriptional factor-mediated regulation of Apaf-1 and PC-9 expression levels plays an important role in predisposition of cells to activate the apoptosome apparatus (4-8). However, the processes of apoptosome assembly and functioning in cancer cells are under a variety of negative and positive modes of post-translational regulation (9,10). There is evidence that the hypersensitivity of certain malignant neoplasms such as brain tumours and breast carcinomas, as opposed to their normal tissue counterparts, to the cyt-c-induced apoptosis is due to up-regulation of Apaf-1 and its regulator PHAPI, respectively, in cancer cells (11,12). On the other hand, deficient signalling in the apoptosome pathway, due to the lack of apoptosome core component expression or apoptosome dysfunction, contributes to tumourigenesis and progression of malignant neoplasms as well as to their chemo-and radioresistance (8,(13)(14)(15)(16)(17)(18)(19)(20).The activation of apoptosome apparatus is often impaired in non-small cell lung carcinoma (NSCLC) cells and tissues (21,22). The molecular basis of apoptosome apparatus suppression in NSCLC is sti...

show abstract

“…Thus, combination regimens have the advantage over a single agent to treat cancer. In addition, it has been shown that 5-aza-CdR sensitizes lung cancer cells to cisplatin and paclitaxel, but the underlying mechanisms are not fully understood (26).…”

Section: Introductionmentioning

confidence: 99%

Evidence that Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Induction by 5-Aza-2′-Deoxycytidine Sensitizes Human Breast Cancer Cells to Adriamycin

Zhou

Tainsky

et al. 2007

Cancer Research

View full text Add to dashboard Cite

The DNA methyltransferase inhibitor 5-aza-2 ¶-deoxycytidine (5-aza-CdR) inhibits DNA methyltransferase activity and sensitizes cancer cells to chemotherapy, but the mechanisms of its sensitization are not fully understood. Here, we show that 5-aza-CdR induces tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in the human breast cancer MDA-231 cells. Induction of TRAIL by 5-aza-CdR correlated with inactivation of Akt. Furthermore, we show that overexpression of the active form of Akt by adenovirus infection or inhibition of the Akt downstream target glycogen synthase kinase 3 by its pharmacologic inhibitors abolishes TRAIL induction by 5-aza-CdR. Importantly, we show that the combined treatment of breast cancer cells with 5-aza-CdR and Adriamycin significantly increases apoptotic cell death compared with the treatment with either agent alone. Moreover, the combined treatment activated both death receptor and mitochondrial apoptotic pathways, whereas Adriamycin alone activated only the mitochondrial pathway while 5-aza-CdR failed to activate either. More importantly, down-regulation of TRAIL by small interference RNA silencing decreased 5-aza-CdR-mediated Adriamycin-induced caspase activation and apoptosis, thus conferring Adriamycin resistance. Taken together, our results suggest that induction of TRAIL by 5-aza-CdR is critical for enhancing chemosensitivity of breast cancer cells to Adriamycin.

show abstract

5-aza-2′-deoxycytidine upregulates caspase-9 expression cooperating with p53-induced apoptosis in human lung cancer cells

Cited by 68 publications

References 27 publications

Sulforaphane causes a major epigenetic repression of myostatin in porcine satellite cells

Sulforaphane causes a major epigenetic repression of myostatin in porcine satellite cells

Down-regulated expression of apoptosis-associated genes APIP and UACA in non-small cell lung carcinoma

Evidence that Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Induction by 5-Aza-2′-Deoxycytidine Sensitizes Human Breast Cancer Cells to Adriamycin

Contact Info

Product

Resources

About