Inhibition of protein kinase C-α isoform enhances the P-glycoprotein expression and the survival of LoVo human colon adenocarcinoma cells to doxorubicin exposure

Abstract

Summary The aim of the present paper was to analyse the effect of long-term inhibitory treatment, for at least 7 days, of individual protein kinase C (PKC) isoforms on the survival of LoVo human colon adenocarcinoma cells to doxorubicin exposure. The treatment for 2 h, after plating the cells, and after 3 days with 1 gM Go6976, a specific inhibitor of protein kinase C (PKC)-a and -i1 isoforms, induced on day 7 in LoVo cell lines (WT) a significant increased survival when these cells were exposed to increasing doxorubicin concentrations. In contrast. resistant LoVo cells (DX) did not show significant changes in the survival to doxorubicin exposure when incubated with the inhibitor of the same specific PKC isoforms. In addition, G66976 reduced the PKC-a activity (the main calcium-dependent PKC isoforms expressed) in both cell lines with contemporary increased expression. Under such conditions. an increased nuclear activity and an increased P-glycoprotein expression occurred only in WT-treated cells with respect to untreated cells. Taken together, our data indicate a specific relationship between PKC-a inhibition, the increased nuclear PKC-a activity as well as the increased expression of P-glycoprotein. possibly causing the acquisition of a resistant phenotype in WT LoVo cells.

Protein Kinase Cα Protects Against Multidrug Resistance in Human Colon Cancer Cells

“…6B). These results are in agreement with previously published work (La Porta et al, 1998) that indicated PKCα plays a pivotal role in drug resistance and mediation of anti-apoptotic events in doxorubicin treated cells. Furthermore, inhibition of PKCα led to increased cleavage of PARP in both types of cells (Fig.…”

Non-histone nuclear factor HMGB1 is phosphorylated and secreted in colon cancers

“…[30][31][32][33] However, some reports have indicated that PKC isoforms are located in the nucleus or are translocated to the nucleus. Similarly, other reports have suggested a direct relationship between nuclear PKC and tumorigenesis, [34][35][36][37] although the regulatory role of nuclear PKC in cancer is not completely understood. [34][35][36][37][38][39] In this study, we showed that HMGB1 interacted with PKC.…”

“…Similarly, other reports have suggested a direct relationship between nuclear PKC and tumorigenesis, [34][35][36][37] although the regulatory role of nuclear PKC in cancer is not completely understood. [34][35][36][37][38][39] In this study, we showed that HMGB1 interacted with PKC. Future functional analysis for the relationship between the specific type of PKC and nuclear phosphorylation might provide valuable information about the role of HMGB1 in tumor progression and invasion.…”

Protein Kinase C (PKC) Isozymes and Cancer

“…PKC isozymes and cancer, PKC isozymes, especially PKC and , are involved in the Pgp-mediated MDR in several types of cancer, such as colon cancer [119][120][121], pancreatic cancer [399], gastric cancer [157], breast cancer [55], leukemia [513], and prostate cancer [447]. In general, inhibition of PKC isozymes that regulate P-gp leads to reduced MDR and enhanced cancer cell apoptosis.…”

“…PKC also regulates transforming growth factor (TGF)-1-induced expression of the matrix adhesion molecules, fibronectin and laminin, leading to the induction of E-cadherin [117,118]. In addition, PKC can induce Pgp-mediated MDR in human colon cancer cells [119][120][121]; thus, downregulation of PKC may increase the sensitivity to anticancer agents [122].…”