PKC-δ inhibits anchorage-dependent and -independent growth, enhances differentiation, and increases apoptosis in CaCo-2 cells

Cerda, Sonia R.; Bissonnette, Marc; Scaglione-Sewell, B.; Lyons, Matthew R.; Khare, Sharad; Mustafi, Reba; Brasitus, Thomas A.

doi:10.1053/gast.2001.24843

Cited by 52 publications

(77 citation statements)

References 49 publications

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“…For instance, PKC␦ overexpression inhibits Sindbs virus-induced apoptosis but enhances etoposide-induced apoptosis in the same cell line (61,62). A recent study showed that increased expression of the PKC␦ isoform enhanced the rate of apoptosis in the Caco-2 human colon cancer cell line, which was further augmented by phorbol ester treatment (28). Future studies will be required to elucidate the cellular effect (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…The novel PKCs ␦, ⑀, , and are Ca 2ϩ -independent but PMA-responsive, whereas the atypical PKC isoforms and do not depend on Ca 2ϩ or respond to PMA (24). PKC␦, a member of the novel PKCs, has been associated with apoptosis, cell transformation, growth arrest, and differentiation of various cell types (25)(26)(27)(28). For example, PKC␦ acts as a pro-survival factor in human breast tumor cells (29).…”

mentioning

confidence: 99%

“…Inhibition of PKC␦ with rottlerin or transfection of a kinasedead mutant of PKC␦ increased apoptosis and potentiated chemotherapy-induced apoptosis in non-small cell lung cancer cells (30). In contrast, overexpression of PKC␦ inhibited the proliferation of fibroblasts (31), induced monocytic differentiation of the myeloid progenitor cell line (17), and enhanced enterocyte-like differentiation of colon cancer cell line Caco-2 (28). PKC␦ has been reported to undergo tyrosine phosphorylation in response to various stimuli such as PMA, epidermal growth factor, and PDGF (17,32,33).…”

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Induction of cIAP-2 in Human Colon Cancer Cells through PKCδ/NF-κB

Wang

Evers

2003

Journal of Biological Chemistry

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Activation of protein kinase C (PKC) prevents apoptosis in certain cells; however, the mechanisms are largely unknown. Inhibitors of apoptosis (IAP) family members, including NAIP, cIAP-1, cIAP-2, XIAP/hILP, survivin, and BRUCE, block apoptosis by binding and potently inhibiting caspases. Activation of NF-B contributes to cIAP-2 induction; however, the cellular mechanisms regulating cIAP-2 expression have not been entirely defined. In this study, we examined the role of the PKC and NF-B pathways in the regulation of cIAP-2 in human colon cancers. We found that cIAP-2 mRNA levels were markedly increased in human colon cancer cells by treatment with the phorbol ester, phorbol-12-myristate-13-acetate (PMA), or bryostatin 1. Inhibitors of the Ca 2؉ -independent, novel PKC isoforms, but not inhibitors of MAPK, PI3-kinase, or PKA, blocked PMA-stimulated cIAP-2 mRNA expression, suggesting a role of PKC in PMA-mediated cIAP-2 induction. Pretreatment with the PKC␦-selective inhibitor rottlerin or transfection with an antisense PKC␦ oligonucleotide inhibited PMA-induced cIAP-2 expression, whereas cotransfection with a PKC␦ plasmid induced cIAP-2 promoter activity, which, taken together, identifies a role for PKC␦ in cIAP-2 induction. Treatment with the proteasome inhibitor, MG132 or inhibitors of NF-B (e.g. PDTC and gliotoxin), decreased PMA-induced up-regulation of cIAP-2. PMAinduced NF-B activation was blocked by either GF109203x, MG132, PDTC, or gliotoxin. Moreover, overexpression of PKC␦-induced cIAP-2 promoter activity and increased NF-B transactivation, suggesting regulation of cIAP-2 expression by a PKC␦/NF-B pathway. In conclusion, our findings demonstrate a role for a PKC/NF-B-dependent pathway in the regulation of cIAP-2 expression in human colon cancer cells. These data suggest a novel mechanism for the anti-apoptotic function mediated by the PKC␦/NF-B/cIAP-2 pathway in certain cancers.

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Section: Discussionmentioning

confidence: 99%

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Induction of cIAP-2 in Human Colon Cancer Cells through PKCδ/NF-κB

Wang

Evers

2003

Journal of Biological Chemistry

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“…In vitro overexpression of PKC-d has been associated with decreased growth and enhanced differentiation and cell death in several noncolonic cell lines (Gschwendt, 1999;Kikkawa et al, 2002;Brodie and Blumberg, 2003;Jackson and Foster, 2004). Our own studies, moreover, have established that PKC-d regulates the growth phenotype in Caco-2 colon cancer cells (Cerda et al, 2001). This human colon cancer cell line has been extensively studied as a model of intestinal epithelial cell biology (Pinto et al, 1983;Evers et al, 1996;Abraham et al, 1998;Ding et al, 1998;ScaglioneSewell et al, 1998).…”

Section: Introductionmentioning

confidence: 93%

Protein kinase C delta inhibits Caco-2 cell proliferation by selective changes in cell cycle and cell death regulators

et al. 2006

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PKC-d is a serine/threonine kinase that mediates diverse signal transduction pathways. We previously demonstrated that overexpression of PKC-d slowed the G1 progression of Caco-2 colon cancer cells, accelerated apoptosis, and induced cellular differentiation. In this study, we further characterized the PKC-d dependent signaling pathways involved in these tumor suppressor actions in Caco-2 cells overexpressing PKC-d using a Zn 2 þ inducible expression vector. Consistent with a G1 arrest, increased expression of PKC-d caused rapid and significant downregulation of cyclin D1 and cyclin E proteins (50% decreases, Po0.05), while mRNA levels remained unchanged. The PKC agonist, phorbol 12-myristate 13-acetate (TPA, 100 nM, 4 h), induced two-fold higher protein and mRNA levels of p21 Waf1, a cyclin-dependent kinase (cdk) inhibitor in PKC-d transfectants compared with empty vector (EV) transfected cells, whereas the PKC-d specific inhibitor rottlerin (3 lM) or knockdown of this isoenzyme with specific siRNA oligonucleotides blocked p21Waf1 expression. Concomitantly, compared to EV control cells, PKC-d upregulation decreased cyclin D1 and cyclin E proteins co-immunoprecipitating with cdk6 and cdk2, respectively. In addition, overexpression of PKC-d increased binding of cdk inhibitor p27Kip1 to cdk4. These alterations in cyclin-cdks and their inhibitors are predicted to decrease G1 cyclin kinase activity. As an independent confirmation of the direct role PKC-d plays in cell growth and cell cycle regulation, we knocked down PKC-d using specific siRNA oligonucleotides. PKC-d specific siRNA oligonucleotides, but not irrelevant control oligonucleotides, inhibited PKCd protein by more than 80% in Caco-2 cells. Moreover, PKC-d knockdown enhanced cell proliferation (B1.4-2-fold, Po0.05) and concomitantly increased cyclin D1 and cyclin E expression (B1.7-fold, Po0.05). This was a specific effect, as nontargeted PKC-f was not changed by PKC-d siRNA oligonucleotides. Consistent with accelerated apoptosis in PKC-d transfectants, compared to EV cells, PKC-d upregulation increased proapoptotic regulator Bax two-fold at mRNA and protein levels, while antiapoptotic Bcl-2 protein was decreased by 50% at a post-transcriptional level. PKC-d specific siRNA oligonucleotides inhibited Bax protein expression by more than 50%, indicating that PKC-d regulates apoptosis through Bax. Taken together, these results elucidate two critical mechanisms regulated by PKC-d that inhibit cell cycle progression and enhance apoptosis in colon cancer cells. We postulate these antiproliferative pathways mediate an important tumor suppressor function for PKC-d in colonic carcinogenesis.

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“…However, there is also literature, largely based on studies with non-mammary cells, suggesting that PKC-d participates in cell death and growth inhibition (Cross et al, 2000;Majumder et al, 2000;Cerda et al, 2001;Blass et al, 2002;DeVries et al, 2002). In some systems, the apoptotic effect of PKC-d has been associated with a cleavage of the catalytic domain from the regulatory domain (Koriyama et al, 1999;Reyland et al, 1999).…”

Section: Role Of Pkc-d In Antiestrogen Resistancementioning

confidence: 99%