Targeting Protein Kinase C (PKC) in Physiology and Cancer of the Gastric Cell System

Abstract

Protein kinase C (PKC) family members are multifunctional kinases that have been implicated in many cell biological and physiological tasks including acid, pepsinogen, and mucous production. Through the use of small-molecule PKC modulators, PKC has been found to be involved in gene expression, the control of cytoskeleton, membrane and secretagogue-dependent signal transduction for secretion of acid. Gastric carcinoma and adenocarcinoma cells often show dysregulated PKC-dependent cell signal transduction compared to normal gastric cells. Moreover, PKC was the first known target of tumor promoting phorbol esters. These findings support PKC as a potential chemotherapy target in gastric cancer. Various approaches have been launched in directly targeting PKC for chemotherapy of gastric cancer. The macrocyclic lactone bryostatin-1 is a promising agent that acts as a modulator of PKC activity, and enhances the effect of chemotherapeutic agents such as paclitaxel. This article provides an overview of the findings to date regarding the physiological role of PKC in the gastric cell system by various pharmacological approaches and examines PKC as a target in gastric (adeno-)carcinoma chemotherapy.

Role of PKCβ in hepatocellular carcinoma cells migration and invasion in vitro: a potential therapeutic target

“…Potentiation of malignant phenotype may be mediated by activation of selective PKC isoenzymes or through altered isoenzyme expression profile compared to the originating tissue [14]. In our gene microarray data, significant difference of only PKCb gene was found in metastatic HCC cells, although several other PKC isozymes have been reported in HCC [15]. These differences may result from different HCC cell lines and experimental conditions.…”

Helicobacter pylori activates protein kinase C delta to control Raf in MAP kinase signalling: Role in AGS epithelial cell scattering and elongation

“…Membrane recruitment of PKC is generally considered as a mechanism for activating multiple PKC isoforms, because this is necessary for getting access to PKC substrates [Li et al, 2003;Steinberg, 2004]. For example, membrane localization of PKC is important for triggering cell migration [Li et al, 2003;Steinberg, 2004], and thus PKC has been linked to cell motility and invasion which are important characteristics of cancer development and metastasis [Herbert, 1993;Musashi et al, 2000;Sullivan et al, 2000;Koivunen et al, 2004;Fahrmann, 2008]. Indeed, the induction of cell motility is also a hallmark of H. pylori-infected gastric epithelial cells in vitro and requires the activities of RTK transmembrane receptors such as EGFR, Her2/ Neu, and c-Met as well as Erk1/2 and the small Rho GTPase Rac1 Churin et al, 2003;Brandt et al, 2007;Backert and Selbach, 2008].…”

Challenges to the development of bryostatin‐type anticancer drugs based on the activation mechanism of protein kinase Cδ

“…8,10 Significant anticancer activities of bryo-1 were observed in phase I trials. However, several phase II studies using bryo-1 alone were disappointing in melanoma, 33 colorectal cancer, 34 and gastric carcinoma.…”

“…35 As the application of paclitaxel followed by bryo-1 significantly reduced tumor growth in mice, 36 phase II studies of bryo-1, in combination with other cytotoxic agents, were tried in pancreatic and prostate cancer, and renal cell and gastric carcinoma. 8,10,35 As a result, an enhanced response to paclitaxel by bryo-1 was observed in advanced gastric or gastroesophageal junction adenocarcinoma in phase II studies. 35 Similar results were obtained for advanced esophageal and gastroesophageal junction cancer.…”