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

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Abstract

PKC-δ is a serine/threonine kinase that mediates diverse signal transduction pathways. We previously demonstrated that overexpression of PKC-δ slowed the G1 progression of Caco-2 colon cancer cells, accelerated apoptosis, and induced cellular differentiation. In this study, we further characterized the PKC-δ dependent signaling pathways involved in these tumor suppressor actions in Caco-2 cells overexpressing PKC-δ using a Zn2+ inducible expression vector. Consistent with a G1 arrest, increased expression of PKC-δ caused rapid and significant downregulation of cyclin D1 and cyclin E proteins (50% decreases, P<0.05), 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 p21Waf1, a cyclin-dependent kinase (cdk) inhibitor in PKC-δ transfectants compared with empty vector (EV) transfected cells, whereas the PKC-δ specific inhibitor rottlerin (3 μ M) or knockdown of this isoenzyme with specific siRNA oligonucleotides blocked p21Waf1 expression. Concomitantly, compared to EV control cells, PKC-δ upregulation decreased cyclin D1 and cyclin E proteins co-immunoprecipitating with cdk6 and cdk2, respectively. In addition, overexpression of PKC-δ 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-δ plays in cell growth and cell cycle regulation, we knocked down PKC-δ using specific siRNA oligonucleotides. PKC-δ specific siRNA oligonucleotides, but not irrelevant control oligonucleotides, inhibited PKC-δ protein by more than 80% in Caco-2 cells. Moreover, PKC-δ knockdown enhanced cell proliferation (∼1.4-2-fold, P<0.05) and concomitantly increased cyclin D1 and cyclin E expression (∼1.7-fold, P<0.05). This was a specific effect, as nontargeted PKC-ζ was not changed by PKC-δ siRNA oligonucleotides. Consistent with accelerated apoptosis in PKC-δ transfectants, compared to EV cells, PKC-δ 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-δ specific siRNA oligonucleotides inhibited Bax protein expression by more than 50%, indicating that PKC-δ regulates apoptosis through Bax. Taken together, these results elucidate two critical mechanisms regulated by PKC-δ 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-δ in colonic carcinogenesis.

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Abbreviations

PKC:

protein kinase C

PKC-δ:

PKC-delta

EV:

empty vector

SDS–PAGE:

sodium dodecyl sulfate–polyacrylamide gel electrophoresis

FACS:

fluorescence-activated cell sorter

BisA:

Bistratene A

TPA:

12-O-tetradecanoylphorbol 13-acetate

IP:

immunoprecipitation

cdk:

cyclin dependent kinase

SS:

scrambled sequence

DAG:

diacylglycerol

PC:

phosphatidylcholine

PI:

phophatidylinositol

PLC:

phospholipase C

RTK:

receptor tyrosine kinase

GPCR:

G protein coupled receptors

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Acknowledgements

This research was supported in part by National Institutes of Health Grant 2R01CA36745 (MB), the American Cancer Society Illinois Division Grant 04-14 (SRC), and the Digestive Disease Research Core Center Grant P30DK42086 at the University of Chicago.

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  1. Department of Medicine, Division of Gastroenterology, University of Chicago, Chicago, IL, USA

    S R Cerda, R Mustafi, H Little, G Cohen, C Moore, P Majumder & M Bissonnette

  2. Department of Medicine, Division of Gastroenterology, Loyola University Medical Center, Maywood, IL, USA

    S Khare

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  1. S R Cerda
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  2. R Mustafi
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Cerda, S., Mustafi, R., Little, H. et al. Protein kinase C delta inhibits Caco-2 cell proliferation by selective changes in cell cycle and cell death regulators. Oncogene 25, 3123–3138 (2006). https://doi.org/10.1038/sj.onc.1209360

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