1. ¹Department of Pediatrics, Oregon Health Sciences University, Portland, OR, USA
2. ²Oregon Cancer Center, Oregon Health Sciences University, Portland, OR, USA
3. ³Earle A Chiles Research Institute, Portland, OR, USA
4. ⁴Istituto Auxologico Italiano Piancavallo, Oggebbio, VB, Italy
5. ⁵Department of Pathology, Virginia Commonwealth University, Richmond, VA, USA

Correspondence: Dr Y Oh, Department of Pathology, Medical College of Virginia Campus, Virginia Commonwealth University, PO Box 980622, Sanger Hall, Room 4-020, 1101 East Marshall Street, Richmond, VA 23298-0662, USA. E-mail: yoh@vcu.edu

Received 4 May 2005; Revised 27 September 2005; Accepted 27 September 2005; Published online 21 November 2005.

Abstract

The need to develop more effective therapies for lung cancer has led to investigations in understanding the molecular mechanisms of the differentiation process, in particular neuroendocrine (NE) differentiation. Recent studies have demonstrated that NE differentiation in non-small cell lung carcinoma (NSCLC) is not uncommon. Those NSCLCs with NE differentiation are considered a form of in transition NE carcinoma and show a more aggressive clinical course compared with NSCLC without NE differentiation. 25.1, a novel protein interacting with mac25/insulin-like growth factor-binding protein-related protein 1 (mac25/IGFBP-rP1), induced NE-like differentiation when collectively overexpressed in M12 prostate cancer cells. We have examined mac25/IGFBP-rP1 and 25.1 as potential molecular regulators in vitro of the NE-differentiation process in lung cancer. In a panel of SCLC and NSCLC cell lines, mac25/IGFBP-rP1 and 25.1 were expressed at higher levels in SCLC. An increase and sustained activation of adenosine 3',5'-cyclic monophosphate (cAMP) levels induced NE-like differentiation in NSCLC cell lines, and a concomitant increase in the expression of mac25/IGFBP-rP1 and 25.1 was observed during the cAMP-regulated differentiation of NCI-H157 cells, suggesting the involvement of these proteins. Furthermore, the collective overexpression of mac25/IGFBP-rP1 and 25.1 in NSCLC cells induced NE-like differentiation as early as 6 h postinfection. The present data suggest that mac25/IGFBP-rP1 and 25.1 may play a functional role in the NE differentiation of NSCLC cell lines and may provide a novel therapeutic target for treating lung cancers, in particular NSCLC with NE differentiation.