1. ¹Department of Medicine (Cancer Research), West German Cancer Center, University Hospital Essen, 45122 Essen, Germany
2. ²Department of Medicine III, Johannes Gutenberg University, 55101 Mainz, Germany
3. ³Department of Human Genetics, Johannes Gutenberg University, 55101 Mainz, Germany
4. ⁴Department of Pathology, Johannes Gutenberg University, 55101 Mainz, Germany

Correspondence: M Schuler, Department of Medicine (Cancer Research), West German Cancer Center, University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany. Tel: +49 201 723 2001; Fax: +49 201 723 5924; E-mail: martin.schuler@uk-essen.de

⁵Present address: LADR GmbH, MVZ Dr. Kramer & Kollegen, Lauenburger Strasse 67, 21502 Geesthacht, Germany.

Received 31 January 2007; Revised 28 August 2007; Accepted 20 September 2007; Published online 26 October 2007.

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.