Protein Kinase A-Mediated Effects of Protein Kinase C Partial Agonist 5-(Hydroxymethyl)Isophthalate 1a3 in Colorectal Cancer Cells.

Colorectal cancer is the third most commonly occurring cancer in men and the second in women. The global burden of colorectal cancer is projected to increase to over 2 million new cases with over 1 million deaths within the next 10 years, and there is a great need for new compounds with novel mechanisms of action. Our group has developed protein kinase C (PKC)-modulating isophthalic acid derivatives that induce cytotoxicity toward human cervical and prostate cancer cell lines. In this study, we investigated the effects of 5-(hydroxymethyl)isophthalate 1a3 (HMI-1a3) on colorectal cancer cell lines (Caco-2, Colo205, and HT29). HMI-1a3 inhibited cell proliferation, decreased cell viability, and induced an apoptotic response in all studied cell lines. These effects, however, were independent of PKC. Using serine/threonine kinome profiling and pharmacological kinase inhibitors, we identified activation of the cAMP/PKA pathway as a new mechanism of action for HMI-1a3-induced anticancer activity in colorectal cancer cell lines. Our current results strengthen the hypothesis for HMI-1a3 as a potential anticancer agent against various malignancies. SIGNIFICANCE STATEMENT: Colorectal cancer (CRC) is a common solid organ malignancy. This study demonstrates that the protein kinase C (PKC)-C1 domain-targeted isophthalatic acid derivative 5-(hydroxymethyl)isophthalate 1a3 (HMI-1a3) has anticancer activity on CRC cell lines independently of PKC. We identified PKA activation as a mechanism of HMI-1a3-induced anticancer effects. The results reveal a new anticancer mechanism of action for the partial PKC agonist HMI-1a3 and thus provide new insights for the development of PKC and PKA modulators for cancer therapy.