Antisense Oligonucleotides Targeting RI Subunit of Protein Kinase A: In Vitro and In Vivo Anti-Tumor

cAMP-dependent protein kinase (PKA) is involved in various cellular functions such as cell proliferation, gene induction, and metabolism (1 ,2 ) and its regulatory subunits have been suggested as a drug target for cancer and other diseases (3 ). PKA is composed of two catalytic (C) and two regulatory (R) subunits and has type I and type II isozymes, with different R subunits, termed RI and RII, interacting with an identical C subunit (1 ). Thus far, four isoforms of R subunits, RIα, RIβ, RIIα, and RIIβ, have been identified. Studies have shown that the RI- and RII-regulatory subunits of PKA have opposite roles in cell growth and differentiation, with RI being growth stimulatory and RII being growth-inhibitory (3 ). Increased expression of the RIα subunit of PKA has been shown during chemical or viral carcinogenesis and correlated with cell proliferation and neoplastic growth (3 ). The RIα subunit of PKA is overexpressed in a variety of human tumor tissues and cell lines, including lung (4 ), breast (5 –7 ), ovarian (8 ,9 ), and colon (10 –12 ). Furthermore, RIβ subunit of PKA overexpression has been shown to correlate with malignancy and worse prognosis in cancer patients (5 –9 ). More recently, studies suggest that extracellular PKA activity may serve as a diagnostic and prognostic marker for cancer (13 ). In addition, RIβ subunit has shown to be associated with multidrug resistance and decreased tumor sensitivity to chemotherapeutic agents (14 –16 ). Therefore, the RIα subunit of PKA is a potential target for human cancer therapy, with several selective type I PKA inhibitors being tested both in preclinical and clinical settings (2 ,3 ,17 –25 ).