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This Article Full Text Full Text (PDF) All Versions of this Article: 287/6/C1616    most recent 00300.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Hastings, R. H. Articles by Deftos, L. J. Search for Related Content PubMed PubMed Citation Articles by Hastings, R. H. Articles by Deftos, L. J.

GROWTH, DIFFERENTIATION, AND APOPTOSIS

Parathyroid hormone-related protein regulates apoptosis in lung cancer cells through protein kinase A

¹Research, ²Anesthesiology, and ³Medicine Services, Department of Veterans Affairs San Diego Healthcare System, San Diego 92161; and Departments of ⁴Anesthesiology and ⁵Medicine, University of California-San Diego, La Jolla, California 92093

Submitted 24 June 2004 ; accepted in final form 24 July 2004

Parathyroid hormone-related protein (PTHrP)-(1–34) and PTHrP-(140–173) protect lung cancer cells from apoptosis after ultraviolet (UV) irradiation. This study evaluated upstream signaling in PTHrP-mediated alteration of lung cancer cell sensitivity to apoptosis. The two peptides increased cAMP levels in BEN lung cancer cells by 15–35% in a dose-dependent fashion, suggesting signaling through protein kinase A (PKA). In line with this view, the PKA inhibitor H89 abrogated the protective effects of PTHrP-(1–34) and PTHrP-(140–173) against caspase activation and DNA loss. PKA activation by forskolin, 3-isobutyl-1-methylxanthine (IBMX), or 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate attenuated and H89 augmented apoptosis after UV exposure as indicated by caspase-3 activation, cell DNA loss, and morphological criteria. Studies with IBMX and varying doses of forskolin indicated that small increases in cAMP, on the order of those generated by IBMX alone and the PTHrP peptides, were sufficient to protect lung cancer cells from apoptosis. In summary, PTHrP-(1–34) and PTHrP-(140–173) stimulate PKA in lung carcinoma cells and protect cells against UV-induced caspase-3 activation and DNA fragmentation. PKA activation by other means also induces resistance to apoptosis, and the protective effect of the PTHrP peptide is blocked by PKA inhibition. Thus PKA appears to have a role in the regulatory effects of PTHrP on lung cancer cell survival.

caspases; cell surface receptors; growth substances; signal transduction