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

Oncogene volume 23, pages 6779–6787 (2004)Cite this article

Abstract

Treating lung cancer cell lines using low-dose 5-aza-2′-deoxycytidine (DAC) caused an accumulation of procaspase-9 through mRNA upregulation, but the cells did not undergo apoptosis. However, when cells were treated with DAC and infected with a low dose of a recombinant wild-type p53 adenovirus vector (Ad-p53), a synergistic growth inhibitory effect was observed. Combination treatment induced Apaf-1 and procaspase-9 expression in which cytochrome c releases by Ad-p53 triggered the mitochondrial pathway of apoptosis. Selective blockage of caspase-9 activities by Z-LEHD-FMK completely attenuated DAC-induced enhancement of apoptosis mediated by Ad-p53 infection, and ectopic overexpression of procaspase-9 sensitized cells to Ad-p53-induced apoptosis in p53-null cells. In addition, DAC sensitized lung cancer cells to cisplatin and paclitaxel. Induction of the mitochondrial pathway of apoptosis using a slightly toxic dose of DAC may therefore be a strategy for treating lung cancer, and DAC treatment may have clinical implications when combined with chemotherapy or apoptosis-inducing gene therapy.

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Acknowledgements

We thank Dr Masahiko Nishizaki for technical advice, and Carmelita Concepcion and Peggy James for the preparation of this manuscript. This work was partially supported by a grant from the National Cancer Institute, National Institutes of Health (PO1 CA78778-01A1; to JAR), the SPORE grant (2P50-CA70970-04), a developmental grant from the National Cancer Institute to MD Anderson Cancer Center SPORE in lung cancer; P50-CA70907 to TM, the Cancer Center Support Core Grant CA 16672 to the Division of Surgery at MD Anderson, a grant from the Tobacco Settlement Funds as appropriated by the Texas Legislature (Project 8), the WM Keck Foundation, and a sponsored research agreement with Introgen Therapeutics, Inc. (SR93-004-1).

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  1. Tapas Mukhopadhyay

    Present address: National Center for Human Genome Studies and Research, Panjab University Pharmaceutical Extension, Block Sector 14, Chandigarh, 160014, India

  2. Yoshihito Gomyo and Ji-ichiro Sasaki: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Thoracic and Cardiovascular Surgery and Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, 77030, TX, USA

    Yoshihito Gomyo, Ji-ichiro Sasaki, Cynthia Branch, Jack A Roth & Tapas Mukhopadhyay

  2. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, 77030, TX, USA

    Jack A Roth

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Correspondence to Ji-ichiro Sasaki.

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Gomyo, Y., Sasaki, Ji., Branch, C. et al. 5-aza-2′-deoxycytidine upregulates caspase-9 expression cooperating with p53-induced apoptosis in human lung cancer cells. Oncogene 23, 6779–6787 (2004). https://doi.org/10.1038/sj.onc.1207381

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