INTERLEUKIN-24 PROMOTES TUMOR CELL-SPECIFIC APOPTOSIS THROUGH PROTEIN KINASE A PATHWAY

Interleukin-24 (IL-24) is a tumor suppressing protein that is currently in phase II clinical trials. The clinical trials have been limited to repeat intratumoral injections in patients with metastatic melanoma. Therefore, despite IL-24’s unique broad cancer-specific apoptotic properties demonstrated in preclinical studies, it is clear that approaches to enhance the therapeutic benefit and clinical implementation of IL-24 are necessary to maximize its effectiveness and to extend the significant results seen in melanoma to multiple cancer types. To maximize IL-24-mediated therapeutic outcomes, we propose to unveil the underlying mechanism of IL-24. We hypothesize that cAMP-dependent protein kinase/protein kinase A (PKA) activity contributes to IL-24 induction of apoptosis. The present studies reveal that PKA is required for Ad.IL-24-induced cell death. Moreover, inhibition of PKA impaired IL-24-induced apoptosis. Activated PKA is known to inactivate glycogen synthase kinase 3-alpha and beta (GSK-3α/β) by phosphorylating serine 21 and 9, which has been implicated in tumor progression, denoting the possible oncogenic characteristics of GSK-3α/β. We show that in response to Ad.IL-24 treatment, GSK-3α/β is inactivated in cancer cells. This effect is reversed when specific PKA inhibitor H-89 is used in conjunction with IL-24 treatment. IL-24 promotes phosphorylation of the anti-apoptotic molecule p53 at serine 15 (phospho-p53^Ser15), a downstream PKA-mediated pathway of IL-24 action. Overall, our novel findings show that IL-24’s selective killing effect is related to PKA activation and subsequent GSK-3α/β inactivation, and phospho-p53^Ser15 activation, which has important implications for our understanding of IL-24 as a tumor suppressor protein.