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Research Articles: Targets

Genes regulated by hepatocyte growth factor as targets to sensitize ovarian cancer cells to cisplatin

¹ Laboratory of Cancer Genetics and ² Division of Molecular Oncology, Institute for Cancer Research and Treatment, University of Torino School of Medicine, Candiolo (Turin), Italy; ³ Department of Clinical and Biological Sciences, University of Torino, Orbassano (Turin), Italy; ⁴ Gene Expression Core-Human Molecular Genetics Laboratory, Institute of Genetics and Biophysics "A.B.T.," Consiglio Nazionale delle Ricerche, Naples, Italy; and ⁵ Department of Genetics, Biology, and Biochemistry, University of Torino, Turin, Italy

Requests for reprints: Maria Flavia Di Renzo, Laboratory of Cancer Genetics, Institute for Cancer Research and Treatment, University of Torino School of Medicine, SP 142, KM 3.95, 10060, Candiolo (Torino), Italy. Phone: 39-11-993-3343; Fax: 39-11-993-3524. E-mail: mariaflavia.direnzo{at}ircc.it

Advanced ovarian cancers are initially responsive to chemotherapy with platinum drugs but develop drug resistance in most cases. We showed recently that hepatocyte growth factor (HGF) enhances death of human ovarian cancer cell lines treated with cisplatin (CDDP) and that this effect is mediated by the p38 mitogen-activated protein kinase. In this work, we integrated genome-wide expression profiling, in silico data survey, and functional assays to identify transcripts regulated in SK-OV-3 ovarian cancer cells made more responsive to CDDP by HGF. Using oligonucleotide microarrays, we found that HGF pretreatment changes the transcriptional response to CDDP. Quantitative reverse transcription-PCR not only validated all the 15 most differentially expressed genes but also confirmed that they were primarily modulated by the combined treatment with HGF and CDDP and reversed by suppressing p38 mitogen-activated protein kinase activity. Among the differentially expressed genes, we focused functional analysis on two regulatory subunits of the protein phosphatase 2A, which were down-modulated by HGF plus CDDP. Decrease of each subunit by RNA interference made ovarian cancer cells more responsive to CDDP, mimicking the effect of HGF. In conclusion, we show that HGF and CDDP modulate transcription in ovarian cancer cells and that this transcriptional response is involved in apoptosis regulation. We also provide the proof-of-concept that the identified genes might be targeted to either increase the efficacy of chemotherapeutics or revert chemotherapy resistance. [Mol Cancer Ther 2006;5(5):1126–35]

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Note: The present address for T. Ruggiero is Gene Expression Regulation Laboratory, Experimental Oncology, Istituto Nazionale Ricerca sul Cancro, Genova, Italy. The present address for A. Rasolas is Department of Biomedical Sciences, University of Padova, Padova, Italy.

⁶ http://www.tigr.org/software/.

⁷ Supplementary materials for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 1/ 9/06; revised 3/10/06; accepted 3/24/06.