PT  - JOURNAL ARTICLE
AU  - Ilari Tarvainen
AU  - Rebecca C. Nunn
AU  - Raimo K. Tuominen
AU  - Maria H. Jäntti
AU  - Virpi Talman
TI  - Protein Kinase A–Mediated Effects of Protein Kinase C Partial Agonist 5-(Hydroxymethyl)Isophthalate 1a3 in Colorectal Cancer Cells
AID  - 10.1124/jpet.121.000848
DP  - 2022 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 54--62
VI  - 380
IP  - 1
4099  - http://jpet.aspetjournals.org/content/380/1/54.short
4100  - http://jpet.aspetjournals.org/content/380/1/54.full
SO  - J Pharmacol Exp Ther2022 Jan 01; 380
AB  - 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.