© 1995 by Oxford University Press
Journal of the National Cancer Institute, Vol. 87, No. 3, 206-212,
February 1995
© 1995 Oxford University Press
Mechanism of Interferon Beta-Induced Squamous Differentiation and Programmed Cell Death in Human Non—Small—Cell Lung Cancer Cell Lines
Affiliations of authors: Department of Human Oncology, Medical College of Pennsylvania-Allegheny Campus, the Allegheny-Singer Research Institute, Pittsburgh: and Veterans Administration Medical Center, Pittsburgh, Pa.
Correspondence to: Mark L. Levitt, M.D., Ph.D., Allegheny General Hospital, 320 E. North Ave., Pittsburgh, PA 15212.
Background: Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality due largely to the failure of systemic chemotherapy. Thus, new therapeutic paradigms involving the manipulation of normal physiologic growth-regulatory mechanisms, such as terminal cellular differentiation or programmed cell death, are being explored. Inter-ferons may function as antineoplastic agents, in part because of their effects on cell proliferation and differentiation. We have previously demonstrated the antiproliferative and differentiating effects of interferon beta (IFN 
). Purpose: The present investigation was designed to study the mechanism of IFN p on squamous differentiation and/or programmed cell death in cultured NSCLC cells. Methods: Cross-linked envelope competence and trans-glutaminase expression and activity were measured in three NSCLC cell lines (NCI-H226, NCI-H358, and NCI-H596) as common markers for squamous differentiation and programmed cell death. DNA fragmentation, as determined by gel electrophoretic analysis, served as a marker for programmed cell death. In addition, the expression of several regulatory and differentiation-related genes (measured by Northern blot analysis of messenger RNA levels) as well as protein kinase Cactivity was measured to begin to explore possible mechanisms of IFN activity. Results: IFN -induced crosslinked envelope competence occurred in cell lines with squamous features (NCI-H226 and NCI-H596); conversely, DNA fragmentation occurred in cell lines with glandular features (NCI-H358 and NCI-H596). Stimulation of cross-linked envelope competence by IFN was associated with the induction of tissue transglutaminase activity. Both of these parameters were protein-synthesis independent. As previously observed for NCI-H596, IFN suppressed the growth of the other two cell lines. Total protein kinase C activity was not altered. Expression of a variety of possibly relevant oncogenes and other genes was variably altered by IFN . Conclusions: IFN induces programmed cell death in NSCLC cell lines in a phenotype-specific manner. The programmed cell death pathway represented by cross-linked envelope competence is dependent on the expression of the squamous phenotype and is protein-synthesis independent, suggesting post-translational mechanisms. In addition, squamous differentiation itself may be induced. Changes in gene expression, while not necessary for induction of cross-linked envelope competence, may be involved in other aspects of cellular homeostasis, such as growth suppression. Implications: By inducing terminal cellular differentiation or programmed cell death, IFN may be therapeutically useful in NSCLC. The post-translational nature of IFN -induced effects suggests that it will be best used in combination with other agents that can regulate these cellular pathways at the pretranslational level, increasing the proportion of cells capable of being driven to a terminal state by this biotherapeutic agent. (J Natl Cancer Inst 87: 206–212, 1995)
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