The second messenger cAMP promotes apoptosis of lymphoma and leukemia cells but mechanisms that mediate this apoptosis are poorly understood. We thus used wild-type (WT) murine S49 T lymphoma cells and S49 variants that lack PKA and cAMP-promoted responses (kin-) or have normal PKA activity but lack cAMP-promoted-apoptosis (“Deathless”, D-) to examine such mechanisms. Results from DNA microarrays revealed that the largest increase in gene expression induced by 8-CPT-cAMP treatment of WT cells is that of cytotoxic T lymphocyte antigen (CTLA-2α), an inhibitor of cathepsin L-like cysteine proteinases. By contrast, CTLA-2α expression was not increased in kin- S49 cells and only slightly increased in D- S49 cells treated with 8-CPT-cAMP. Real-time PCR and immunoblotting confirmed the prominent cAMP-promoted increase in CTLA-2α expression in WT cells. The β-adrenergic receptor agonist isoproterenol and the adenylyl cyclase activator forskolin also induced CTLA-2α gene expression in WT cells, thus indicating that increased CTLA-2α expression can occur via activation of endogenous activators of the cAMP/PKA signaling pathway. Treatment with an adenoviral construct, Adv-CTLA-2α, induced apoptosis in both WT and D- S49 cells but enhanced cAMP-promoted apoptosis only in WT cells. WT, but not D-, S49 cells treated with 8-CPT-cAMP had increased cathepsin activity. Taken together, these results indicate that the cAMP/PKA pathway up-regulates CTLA-2α expression and based on the contrasting findings obtained with WT vs. D- S49 cells, CTLA-2α may be a key contributor to cAMP/PKA-promoted apoptosis. CTLA-2α and cysteine proteases thus appear to have previously unappreciated roles in apoptosis of lymphoid cells by agents that increase cellular cAMP levels.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1213.