Dichotomous role of protein kinase A type I (PKAI) in the tumor microenvironment: A potential target for 'two-in-one' cancer chemoimmunotherapeutics

An emerging trend in cancer chemoimmunotherapeutics is to develop 'two-in-one' therapies, which directly inhibit tumor growth and progression, as well as enhance anti-tumor immune surveillance. Protein kinase A (PICA) is a cAMP-dependent protein kinase that mediates signal transduction of G-protein coupled receptors (GPCRs). The regulatory subunit of PICA exists in two isoforms, RI and Rh, which distinguish the PICA isozymes, PICA type I (PKAI) and PICA type II (PICAII). The differential expression of both PICA isozymes has long been linked to growth regulation and differentiation. RI/PKAI is particularly implicated in cellular proliferation and neoplastic transformation. Emerging experimental and pre-clinical data also indicate that RI/PKAI plays a key role in tumor-induced immune suppression. More briefly, RI/PICA' possesses a dichotomous role in the tumor microenvironment: not only contributes to tumor growth and progression, but also takes part in tumor-induced suppression of the innate and adaptive arms of antitumor immunosurveillance. This review specifically discusses this dichotomous role of RI/PKAI with respect to 'two-in-one' chemoimmunotherapeutic manipulation. The reviewed experimental and pre-clinical data provide the proof of concept validation that RI/PKAI may be regarded as an attractive target for a new, single-targeted, 'two hit' chemoimmunotherapeutic approach against cancer. (C) 2015 Elsevier Ireland Ltd. All rights reserved.