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Regulation of p53 and suppression of apoptosis by the soluble guanylyl cyclase/cGMP pathway in human ovarian cancer cells

Oncogene volume 25, pages 2203–2212 (2006)Cite this article

Abstract

Dysregulated apoptosis plays a critical role in the development of a number of aberrant cellular processes, including tumorigenesis and chemoresistance. However, the mechanisms that govern the normal apoptotic program are not completely understood. Soluble guanylyl cyclase (sGC) and cyclic guanosine monophosphate (cGMP) promote mammalian cell viability via an unknown mechanism and p53 status is a key determinant of cell fate in human ovarian cancer cells. Whether an interaction exists between these two determinants of cell fate is unknown. We hypothesized that basal sGC activity reduces p53 content and attenuates p53-dependent apoptosis in human ovarian cancer cells. Suppression of sGC activity with the specific inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) lowered cGMP content, and increased p53 protein content and induced apoptosis in three ovarian cancer cell lines, effects which were attenuated by the cGMP analog 8-Br-cGMP and by Atrial Natriuretic Factor, an activator of particulate guanylyl cyclase, which circumvent the inhibition of sGC. ODQ prolonged p53 half-life, induced phosphorylation of p53 on Ser15, and upregulated the p53-dependent gene products p21, murine double minute-2, and the proapoptotic, p53-responsive gene product Bax. ODQ activated caspase-3, and ODQ-induced apoptosis was inhibited by overexpression of X-linked inhibitor of apoptosis Protein. Pretreatment with the specific p53 inhibitor pifithrin or downregulation of p53 using a specific small inhibitory RNA significantly attenuated ODQ-induced apoptosis. Moreover, ODQ-induced upregulation of p21 and Bax and ODQ-induced apoptosis were significantly reduced in a p53 mutant cell line relative to the wild-type parental cell line. Thus, the current study establishes that basal sGC/cGMP activity regulates p53 protein stability, content, and function, possibly by altering p53 phosphorylation and stabilization, and promotes cell survival in part through regulation of caspase-3 and p53.

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Abbreviations

sGC:

soluble guanylyl cyclase

pGC:

particulate guanylyl cyclase

cGMP:

cyclic guanosine monophosphate

PKG:

protein kinase G

ODQ:

1H-[1,2,4]oxadiazolo[43-a]quinoxalin-1-one

IAP:

inhibitor of apoptosis protein

GAPDH:

glyceraldehyde phosphate dehydrogenase

BNP:

brain natriuretic peptide

ANF:

atrial natriuretic factor

SDS–PAGE:

sodium dodecyl sulfate–polyacrylamide gel electrophoresis

PMSF:

phenylmethylsulfonyl fluoride

RNAi:

RNA interference

siRNA:

small inhibitory RNA

DMEM:

Dulbecco's modified Eagle's medium

ECL:

enhanced chemiluminescence

PFT:

pifithrin-α hydrobromide

PBS:

phosphate-buffered saline

Xiap:

X-linked inhibitor of apoptosis protein

Xiap-s:

adenoviral Xiap sense cDNA

ROS:

reactive oxygen species

MDM2:

murine double minute-2

NO:

nitric oxide

CHX:

cycloheximide

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Acknowledgements

This work was supported in part by grants awarded to Benjamin K Tsang by the Canadian Institutes of Health Research (MOP-15691) and the National Cancer Institute of Canada (with funds from the Canadian Cancer Society, Grant 013335) and to Ronald R Fiscus by the Research Grants Council of Hong Kong (Grant # CUHK4169/02M) and the Graduate School Bursary Sub-Committee of The Chinese University of Hong Kong for the grant for Overseas Academic Activities, awarded to Siu Lan Chan. Michael Fraser is the recipient of a Canada Graduate Scholarship Doctoral Research Award from the Canadian Institutes of Health Research.

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Authors and Affiliations

  1. Reproductive Biology Unit and Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Ottawa, Ottawa, Ontario, Canada

    M Fraser, S L Chan, S S L Chan & B K Tsang

  2. Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada

    M Fraser, S L Chan, S S L Chan & B K Tsang

  3. Hormones, Growth and Development Program, Ottawa Health Research Institute, The Ottawa Hospital (Civic Campus), Ottawa, Ontario, Canada

    M Fraser, S L Chan, S S L Chan & B K Tsang

  4. Department of Physiology (Faculty of Medicine), Epithelial Cell Biology Research Centre and Centre for Gerontology and Geriatrics, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

    S L Chan & R R Fiscus

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Correspondence to B K Tsang.

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Fraser, M., Chan, S., Chan, S. et al. Regulation of p53 and suppression of apoptosis by the soluble guanylyl cyclase/cGMP pathway in human ovarian cancer cells. Oncogene 25, 2203–2212 (2006). https://doi.org/10.1038/sj.onc.1209251

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