Abstract
During malignant transformation, cancer cells have to evade cell-intrinsic tumor suppressor mechanisms including apoptosis, thus acquiring a phenotype that is relatively resistant to clinically applied anticancer therapies. Molecular characterization of apoptotic signal transduction defects may help to identify prognostic markers and to develop novel therapeutic strategies. To this end we have undertaken functional analyses of drug-induced apoptosis in human non-small cell-lung cancer (NSCLC) cells. We found that primary drug resistance correlated with defects in apoptosome-dependent caspase activation in vitro. While cytochrome c-induced apoptosome formation was maintained, the subsequent activation of caspase-9 and -3 was abolished in resistant NSCLC. The addition of recombinant pp32/putative human HLA class II-associated protein (pp32/PHAPI), described as a putative tumor suppressor in prostate cancer, successfully restored defective cytochrome c-induced caspase activation in vitro. Conditional expression of pp32/PHAPI sensitized NSCLC cells to apoptosis in vitro and in a murine tumor model in vivo. Immunohistochemical analyses of tumor samples from NSCLC patients revealed that the expression of pp32/PHAPI correlated with an improved outcome following chemotherapy. These results identify pp32/PHAPI as regulator of the apoptosis response of cancer cells in vitro and in vivo, and as a predictor of survival following chemotherapy for advanced NSCLC.
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Abbreviations
- IRS:
-
immunoreactivity score
- NOD/SCID:
-
non-obese diabetic/severe combined immunodeficiency
- PHAPI:
-
putative human HLA class II-associated protein
- SET:
-
endoplasmic reticulum-associated complex
- Xiap:
-
X-linked Inhibitor of apoptosis
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Acknowledgements
We thank Drs. Klaus-Michael Debatin, Wolfgang Hillen, Judy Lieberman, Gary P Nolan, David C Pallas, Guy S Salvesen, Xiaodong Wang and Beni B Wolf for providing reagents. Monika Kröll, Melanie Guyot, Yvonne Höhn, Alexander Hohberger, Irmtrud Roth, Silke Mitschke and Nicole Koplin are thanked for technical assistance; Dr. Abdo Konur for help with microscopy; Drs. Martin Sebastian, Claudia Döring, Lars-Henning Schmidt and Joachim Makowski for help with the collection of patient data and material; Professor Thomas Haaf and Professor Christoph Huber for support and advice. This work was supported by grants from the Deutsche Krebshilfe (Max-Eder-Gruppe No. 106089), Deutsche Forschungsgemeinschaft (SCHU1541/3-1), and Wilhelm Sander-Stiftung (2005.136.1). MS, AZ, RW, SH, VB designed research and interpreted results; SH, AZ, RW, PSH, VB, MS carried out experiments; AK and SB analyzed data and provided technology; MS supervised the project and wrote the paper.
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Hoffarth, S., Zitzer, A., Wiewrodt, R. et al. pp32/PHAPI determines the apoptosis response of non-small-cell lung cancer. Cell Death Differ 15, 161–170 (2008). https://doi.org/10.1038/sj.cdd.4402256
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DOI: https://doi.org/10.1038/sj.cdd.4402256
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