Drug Research Program and Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Finland (I.T., R.C.N., R.K.T., M.H.J., V.T.)
Drug Research Program and Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Finland (I.T., R.C.N., R.K.T., M.H.J., V.T.).
J Pharmacol Exp Ther. 2022 Jan;380(1):54-62. doi: 10.1124/jpet.121.000848. Epub 2021 Oct 25.
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.
结直肠癌是男性第三大常见癌症，女性第二大常见癌症。预计在未来 10 年内，全球结直肠癌的负担将增加到超过 200 万例新发病例和超过 100 万例死亡病例，因此非常需要具有新作用机制的新化合物。我们的团队开发了蛋白激酶 C（PKC）调节的间苯二甲酸衍生物，这些衍生物对人宫颈和前列腺癌细胞系具有细胞毒性。在这项研究中，我们研究了 5-（羟甲基）间苯二甲酸 1a3（HMI-1a3）对结直肠癌细胞系（Caco-2、Colo205 和 HT29）的影响。HMI-1a3 抑制细胞增殖，降低细胞活力，并诱导所有研究的细胞系发生凋亡反应。然而，这些作用与 PKC 无关。通过丝氨酸/苏氨酸激酶组谱分析和药理学激酶抑制剂，我们确定 cAMP/PKA 途径的激活是 HMI-1a3 诱导结直肠癌细胞系抗癌活性的新作用机制。我们目前的结果支持了 HMI-1a3 作为针对各种恶性肿瘤的潜在抗癌剂的假说。 意义声明：结直肠癌（CRC）是一种常见的实体器官恶性肿瘤。本研究表明，靶向蛋白激酶 C（PKC）C1 结构域的间苯二甲酸衍生物 5-（羟甲基）间苯二甲酸 1a3（HMI-1a3）对 CRC 细胞系具有独立于 PKC 的抗癌活性。我们确定 PKA 的激活是 HMI-1a3 诱导抗癌作用的一种机制。这些结果揭示了 HMI-1a3 的一种新的抗癌作用机制，为开发 PKC 和 PKA 调节剂用于癌症治疗提供了新的见解。
