Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Clinical and Translational Oncology
Published in: Clinical and Translational Oncology 3/2019

01-03-2019 | Review Article

Classical Protein Kinase C: a novel kinase target in breast cancer

Authors: R. K. Singh, S. Kumar, M. S. Tomar, P. K. Verma, S. P. Singh, P. K. Gautam, A. Acharya

Published in: Clinical and Translational Oncology | Issue 3/2019

Login to get access

Abstract

Classical protein kinase C (cPKC) enzymes are ser/thr protein kinases that have been an important factor in regulating a variety of cellular functions required for both in terms of health and disease. Therefore, precise control of cPKC-mediated signal is necessary for cellular homeostasis; however, their dysregulation leads to the development of several pathophysiological conditions including cancer. In cellular microenvironment, cPKC-mediated signaling is accompanied by multiple molecular mechanisms including phosphorylation, second messenger binding, and scaffold proteins. Functional cPKC interacts with a number of cellular proteins involved in the regulation of multiple biological functions such as cell growth, survival, migration, and adhesion. Further, the role of cPKC varies from cell to cell, substrate to substrate and, therefore, it is plausible to assume that the dysregulation of cPKC activity causes cellular transformation. Currently, there is no sufficient literature available to provide better understating to develop an effective therapeutic regimen to reverse pathophysiological condition caused by functionally dysregulated cPKC. Therefore, in the present review, we have focused on to provide a better and detail information on the various aspects of cPKC such as structure, mode of activation, regulation, and distinct cellular functions useful for the development of an effective therapeutic regimen against the breast cancer.
Literature
1.
Dempsey EC, Newton AC, Mochly-Rosen D, Fields AP, Reyland ME, Insel PA, et al. Protein kinase C isozymes and the regulation of diverse cell responses. Am J Physiol Lung Cell Mol Physiol. 2000;279:L429–38.CrossRef
2.
Castagna M, Takai Y, Kaibuchi K, Sano K, Kikkawa U, Nishizuka YD. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters. J Biol Chem. 1982;257(13):7847–51.PubMed
3.
Steinberg SF. Structural basis of protein kinase C isoform function. Physiol Rev. 2008;88:1341–78.CrossRef
4.
Mochly-Rosen D, Das K, Grimes KV. Protein kinase C, an elusive therapeutic target? Nat Rev Drug Discov. 2012;11(12):937–57.CrossRef
5.
Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002;298:1912–34.CrossRef
6.
Freeley M, Kelleher D, Long A. Regulation of Protein Kinase C function by phosphorylation on conserved and non-conserved sites. Cell Signal. 2011;23:753–62.CrossRef
7.
Newton AC. Protein kinase C: poised to signal. Am J Physiol Endocrinol Metab. 2010;298:E395–402.CrossRef
8.
Newton AC. Regulation of the ABC kinases by phosphorylation: proteinkinase C as a paradigm. Biochem J. 2003;370:361–71.CrossRef
9.
Parker PJ, Parkinson SJ. AGC protein kinase phosphorylation and protein kinase C. Biochem Soc Trans. 2001;29:860–3.CrossRef
10.
Good LE, Ziegler JA, Parekh WH, Alessi DB, Cohen DR, Parker PJ. Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science. 1998;281:2042–5.CrossRef
11.
Dutil EM, Toker A, Newton AC. Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1). Curr Biol. 1998;8:1366–75.CrossRef
12.
Scott AM, Antal CE, Newton AC. Electrostatic and hydrophobic interactions differentially tune membrane binding kinetics of the C2 domain of protein kinase Cα. J Biol Chem. 2013;288:16905–15.CrossRef
13.
Orr JW, Keranen LM, Newton AC. Reversible exposure of the pseudosubstrate domain of protein kinase C by phosphatidylserine and diacylglycerol. J Biol Chem. 1992;267:15263–6.PubMed
14.
Lin D, Takemoto DJ. Oxidative activation of protein kinase Cγ through the C1 domain: effects on gap junctions. J Biol Chem. 2005;280:13682–93.CrossRef
15.
Lauer J, Banerjee D, Shanks D, Dai H, Gong YX, Prakash O, et al. NMR structure/function relationships of peptides corresponding to the C1B1 region of PKCγ. Protein Pept Lett. 2010;17:1–10.CrossRef
16.
Ron D, Chen CH, Caldwell J, Jamieson L, Orr E, Mochly-Rosen D. Cloning of an intracellular receptor for protein kinase C: a homolog of the β subunit of G proteins. Proc Natl Acad Sci USA. 1994;91:839–43.CrossRef
17.
Stebbins EG, Mochly-Rosen D. Binding specificity for RACK1 resides in the V5 region of βII protein kinase C. J Biol Chem. 2001;276:29644–50.CrossRef
18.
Ron D, Luo J, Mochly-Rosen D. C2 region-derived peptides inhibit translocation and function of β protein kinase C in vivo. J Biol Chem. 1995;270:24180–7.CrossRef
19.
Chen D, Gould C, Garza R, Gao T, Hampton RY, Newton AC. Amplitude control of protein kinase C by RINCK, a novel E3 ubiquitin ligase. J Biol Chem. 2007;282:33776–87.CrossRef
20.
Luo B, Prescott SM, Topham MK. Association of diacylglycerol kinase ζ with protein kinase Cα: spatial regulation of diacylglycerol signaling. J Cell Biol. 2003;160:929–37.CrossRef
21.
Abrahamsen H, Neill AK, Kannan N, Kruse N, Taylor SS, Jennings PA, et al. Peptidyl-prolyl isomerase Pin1 controls down-regulation of conventional protein kinase C isozymes. J Biol Chem. 2012;287:13262–78.CrossRef
22.
Lu Z, Liu D, Hornia A, Devonish W, Pagano M, Foster DA. Activation of protein kinase C triggers its ubiquitination and degradation. Mol Cell Biol. 1998;18:839–45.CrossRef
23.
Leontieva OV, Black JD. Identification of two distinct pathways of protein kinase Cα down-regulation in intestinal epithelial cells. J Biol Chem. 2004;279:5788–801.CrossRef
24.
Lum MA, Pundt KE, Paluch BE, Black AR, Black JD. Agonist-induced down-regulation of endogenous protein kinase Cα through an endolysosomal mechanism. J Biol Chem. 2013;288:13093–109.CrossRef
25.
Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt–FOXO and PKCα, but not S6K1. Dev Cell. 2006;11:859–71.CrossRef
26.
Balendran A, Hare GR, Kieloch A, Williams MR, Alessi DR. Further evidence that 3-phosphoinositide-dependent protein kinase-1 (PDK1) is required for the stability and phosphorylation of protein kinase C (PKC) isoforms. FEBS Lett. 2000;484:217–23.CrossRef
27.
Nakashima S. Protein kinase Ca (PKCa): regulation and biological function. J Biochem. 2002;132:669–75.CrossRef
28.
Ways DK, Kukoly CA, deVente J, Hooker JL, Bryant WO, Posekany KJ, et al. MCF-7 breast cancer cells transfected with protein kinase C-α exhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype. J Clin Invest. 1995;95:1906–15.CrossRef
29.
Black AR, Black JD. Protein kinase C signaling and cell cycle regulation. Front Immunol. 2013;17(3):423.
30.
Black JD. Protein kinase C- mediated regulation of the cell cycle. Front Biosci. 2000;5:D406–23.CrossRef
31.
Soh JW, Lee YS, Weinstein IB. Effects of regulatory domains of specific isoforms of protein kinase C on growth control and apoptosis in MCF-7 breast cancer cells. J Exp Ther Oncol. 2003;3(3):115–26.CrossRef
32.
Gruber JR, Ohno S, Niles RM. Increased expression of protein kinase C α play a key role in retinoic acid induced melanoma differentiation. J Biol Chem. 1992;267:13356–60.PubMed
33.
Powell CT, Brittis NJ, Stec D, Hug H, Heston WD, Fair WR. Persistant membrane translocation of protein kinase C alpha during 12-O-tetradecanoylphorbol-13-acetate induced apoptosis of LNCaP human prostate cancer cells. Cell Growth Differ. 1996;7:419–28.PubMed
34.
Majewski M, Nieborowska-Skorska M, Salomoni P, Slupianek A, Reiss K, et al. Activation of mitochondrial Raf-1 is involved in the antiapoptotic effects of Akt. Cancer Res. 1999;59:2815–9.PubMed
35.
Mayati A, Moreau A, Le Vée Marc, Stieger B, Denizot C, Parmentier Y, et al. Protein kinases C-mediated regulations of drug transporter activity, localization and expression. Int J Mol Sci. 2017;18:764.CrossRef
36.
Ahmad S, Glazer RI. Expression of the antisense cDNA for protein kinase C alpha attenuates resistance in doxorubicin-resistant MCF-7 breast carcinoma cells. Mol Pharmacol. 1993;43(6):858–62.PubMed
37.
Fogh BS, Multhaupt HAB, Couchman JR. Protein kinase C, focal adhesions and the regulation of Cell Migration. J Histochem Cytochem. 2014;62(3):172–84.CrossRef
38.
Dovas A, Yoneda A, Couchman JR. PKCα -dependent activation of Rho A by syndecan-4 during focal adhesion formation. J Cell Sci. 2017;119:2837–46.CrossRef
39.
Wallis S, Lloyd S, Wise I, Ireland G, Fleming TP, Garrod D. The isoform of protein kinase C is involved in signaling the response of desmosomes to wounding in cultured epithelial cells. Mol Bio Cell. 2000;11:1077–92.CrossRef
40.
Morrison MM, Young CD, Wang S, Sobolik T, Sanchez VM, Hicks DJ, et al. mTOR directs breast morphogenesis through the PKC-alpha-Rac1 signaling axis. PLoS Genet. 2015;11(7):e1005291.CrossRef
41.
Gomez J, Pitton C, Garcia A, Martinez De Aragon A, Silva A, Rebollo A. The zeta isoform of protein kinase C controls interleukin-2-mediatedproliferation in a murine T cell line: evidence for an additional role of protein kinase C epsilon and beta. Exp Cell Res. 1995;218:105–13.CrossRef
42.
Haiyang LI, Weinstein IB. Protein kinase C β enhances growth and expression of cyclin D1 in human breast cancer cells. Cancer Res. 2006;66(23):11399–408.CrossRef
43.
Whitman SP, Civoli F, Daniel LW. Protein kinase C beta II activation by 1-beta—darabinofuranosylcytosine is antagonistic to stimulation of apoptosis and Bcl-2 alpha downregulation. J Biol Chem. 1997;272(23):481–4.
44.
Cao M-Y, Shinjo F, Heinrichs S, Soh J-W, Jongstra-Bilen J, Jongstra J. Inhibition of anti-IgM-induced translocation of protein kinase C beta I inhibits ERK2 activation and increases apoptosis. J Biol Chem. 2001;276(24):506–10.CrossRef
45.
Wallace JA, Pitarresi JR, Sharma N, Palettas M, Cuitiño MC, Steven T, et al. Protein Kinase C beta in the tumor microenvironment promotes mammary tumorigenesis. Front Oncol. 2014;4:87.CrossRef
46.
Vargo-Gogola T, Rosen JM. Modelling breast cancer: one size does not fit all. Nat Rev Cancer. 2007;7:659–72.CrossRef
47.
Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnson H, Hastie T, Eisen MB, van de Rijan M, Jeffrey SS, et al. Gene expression patterns of breast carcinomas distinguish tumor subclass with clinical implication. Proc Natl Acad Sci USA. 2001;98:10869–74.CrossRef
48.
Suga K, Sugimoto I, Ito H, Hashimoto E. Down-regulation of protein kinase C-alpha detected in human colorectal cancer. Biochem Mol Biol Int. 1998;44:523–8.PubMed
49.
von Brandenstein M, Pandarakalam JJ, Kroon L, Loeser H, Herden J, Braun G, et al. MicroRNA 15a, inversely correlated to PKC alpha, is a potential marker to differentiate between benign and malignant renal tumors in biopsy and urine samples. Am J Pathol. 2012;180:1787–97.CrossRef
50.
Kushner PJ, Agard DA, Greene GL, Scanlan TS, Shiau AK, Uht RM, et al. Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol. 2000;74:311–7.CrossRef
51.
Tan M, Li P, Sun M, Yin G, Yu D. Upregulation and activation of PKC alpha by ErbB2 through Src promotes breast cancer cell invasion that can be blocked by combined treatment with PKC alpha and Src inhibitors. Oncogene. 2006;25:3286–95.CrossRef
52.
Humphries B, Wang Z, Oom AL, Fisher T, Tan D, Cui Y, et al. MicroRNA-200b targets protein kinase Cα and suppresses triple-negative breast cancer metastasis. Carcinogenesis. 2014;35:2254–63.CrossRef
53.
Pham TW, Tonetti DA, Protein kinase C alpha (PKCa) is a novel regulator of FOXC2 and p120-catenin in triple negative and endocrine resistant breast cancer. In: proceedings of the 106th annual meeting of the American association for cancer research; 2015.
54.
Ways DK, Kukoly CA, deVente J, Hooker JL, Bryant WO, Posekany KJ, et al. MCF-7 breast cancer cells transfected with protein kinase C-alpha exhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype. J Clin Invest. 1995;95:1906–15.CrossRef
55.
Chisamore MJ, Ahmed Y, Bentrem DJ, Jordan VC, Tonetti DA. Novel antitumor effect of estradiol in a thymic mice injected with a T47D breast cancer cell line overexpressing protein kinase C alpha. Clin Cancer Res. 2001;7:3156–65.PubMed
56.
Yun J, Pannuti A, Espinoza I, Zhu H, Hicks C, Zhu X, et al. Crosstalk between PKC alpha and Notch-4 in endocrine-resistant breast cancer cells. Oncogenesis. 2013;2:e60.CrossRef
57.
Tonetti DA, Morrow M, Kidwai N, Gupta A, Badve S. Elevated protein kinase C alpha expression may be predictive of tamoxifen treatment failure. Br J Cancer. 2003;88:1400–2.CrossRef
58.
Lonne GK, Cornmark L, Zahirovic IO, Landberg G, Jirstrom K, Larsson C. PKC alpha expression is a marker for breast cancer aggressiveness. Mol Cancer. 2010;9:76.CrossRef
59.
Liu B, Maher RJ, Hannun YA, Porter AT, Honn KV. 12(S)-HETE enhancement of prostate tumor cell invasion: selective role of PKC alpha. J Natl Cancer Inst. 1994;86:1145–51.CrossRef
60.
Tam WL, Lu H, Buikhuisen J, Soh BS, Lim E, Reinhardt F, et al. Protein kinase C alpha is a central signaling node and therapeutic target for breast cancer stem cells. Cancer Cell. 2013;24:347–64.CrossRef
61.
Tonetti DA, Gao W, Escarzaga D, Walters K, Szafran A, Coon JS. PKCalpha and ERbeta Are associated with triple-negative breast cancers in African American and Caucasian patients. Int J Breast Cancer. 2012;2012:740353.CrossRef
62.
Pham TND, White BEP, Zhao H, Mortazavi F, Tonetti. DA, et al. Protein kinase C α enhances migration of breast cancer cells through FOXC2- mediated repression of p120-catenin Pham. BMC Cancer. 2017;17:832.CrossRef
63.
Yu W, Murray NR, Weems C, Chen L, Guo H, Ethridge R, Ceci JD, Evers BM, Thompson EA, Fields AP. Role of cyclooxygenase 2 in protein kinase C beta II-mediated colon carcinogenesis. J Biol Chem. 2003;278:11167–74.CrossRef
64.
Espinosa I, Briones J, Bordes R, Brunet S, Martino R, Sureda A, et al. Membrane PKC-beta 2 protein expression predicts for poor response to chemotherapy and survival in patients with diffuse large B-cell lymphoma. Ann Hematol. 2006;85:597–603.CrossRef
65.
Teicher BA, Menon K, Alvarez E, Shih C, Faul MM. Antiangiogenic and antitumor effects of a protein kinase Cbeta inhibitor in human breast cancer and ovarian cancer xenografts. Invest New Drugs. 2002;20:241–51.CrossRef
66.
Kim J, Choi YL, Vallentin A, Hunrichs BS, Hellerstein MK, Peehl DM, Mochly-Rosen D. Centrosomal PKCbetaII and pericentrin are critical for human prostate cancer growth and angiogenesis. Cancer Res. 2008;68:6831–9.CrossRef
67.
Teicher BA, Menon K, Alvarez E, Galbreath E, Shih C, Faul M. Antiangiogenic and antitumor effects of a protein kinase Cbeta inhibitor in human T98G glioblastoma multiforme xenografts. Clin Cancer Res. 2001;7:634–40.PubMed
68.
Li H, Weinstein IB. Protein kinase C beta enhances growth and expression of cyclin D1 in human breast cancer cells. Cancer Res. 2006;66:11399–408.CrossRef
69.
Manni A, Buckwalter E, Etindi R, Kunselman S, Rossini A, Mauger D, et al. Induction of a less aggressive breast cancer phenotype by protein kinase C-alpha and -beta overexpression. Cell Growth Differ. 1996;7:1187–98.PubMed
70.
Gokmen-Polar Y, Mehta R, Tuzmen S, Mousses S, Thorat MA, Sanders KL, et al. Differential subcellular expression of protein kinase C betaII in breast cancer: correlation with breast cancer subtypes. Breast Cancer Res Treat. 2010;124:327–35.CrossRef
71.
Pham Thao ND, Debra A. Tonetti protein kinase C alpha in breast cancer: a focus on endocrine resistant and triple negative breast cancer. J Cancer Biol Res. 2016;4(1):1076.
72.
Hofmann J. Protein kinase C isozymes as potential targets for anticancer therapy. Curr Cancer Drug Targets. 2004;4:125–46.CrossRef
73.
Dowling CM, Kiely PA. Targeting protein kinase C downstream of growth factor and adhesion signalling. Cancers (Basel). 2015;7:1271–91.CrossRef
74.
Karaman MW, Herrgard S, Treiber DK, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008;26:127–32.CrossRef
75.
Dowling CM, Kiely PA. Targeting protein kinase C downstream of growth factor and adhesion signalling. Cancers (Basel). 2015;7:1271–91.CrossRef
76.
Kheifets V, Mochly-Rosen D. Insight into intra- and inter-molecular interactions of PKC: design of specific modulators of kinase function. Pharmacol Res. 2007;55:467–76.CrossRef
77.
Kim J, Thorne SH, Sun L, Huang B, Mochly-Rosen D. Sustained inhibition of PKCα reduces intravasation and lung seeding during mammary tumor metastasis in an in vivo mouse model. Oncogene. 2011;30:323–33.CrossRef
78.
Mahmmoud YA. Modulation of protein kinase C by curcumin; inhibition and activation switched by calcium ions. Br J Pharmacol. 2007;150:200–8.CrossRef
79.
Deka SJ, Mamdi N, Manna D, Trivedi V. Alkyl cinnamates induce protein kinase C translocation and anticancer activity against breast cancer cells through induction of the mitochondrial pathway of apoptosis. J Breast Cancer. 2016;19(4):358–71.CrossRef
80.
Humphries B, Wang Z, Oom AL, Fisher T, Tan D, Cui Y, et al. MicroRNA-200b targets protein kinase Cα and suppresses triple-negative breast cancer metastasis. Carcinogenesis. 2014;35:2254–63.CrossRef
Metadata
Title
Classical Protein Kinase C: a novel kinase target in breast cancer
Authors
R. K. Singh
S. Kumar
M. S. Tomar
P. K. Verma
S. P. Singh
P. K. Gautam
A. Acharya
Publication date
01-03-2019
Publisher
Springer International Publishing
Published in
Clinical and Translational Oncology / Issue 3/2019
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI
https://doi.org/10.1007/s12094-018-1929-x

Other articles of this Issue 3/2019

Clinical and Translational Oncology 3/2019 Go to the issue

Research Article

Differences on metabolic behavior between intra and extrahepatic cholangiocarcinomas at 18F-FDG–PET/CT: prognostic implication of metabolic parameters and tumor markers

Research Article

Postoperative adjuvant and very early salvage radiotherapy after prostatectomy in high-risk prostate cancer patients can improve specific and overall survival

Review Article

Beyond first-line systemic treatment for metastatic urothelial carcinoma of the bladder

Research Article

Baseline 18F-Fluorocholine PET/CT and bone scan in the outcome prediction of patients treated with radium 223 dichloride

Review Article

Chemotherapy management for unfit patients with metastatic castration-resistant prostate cancer

Review Article

Melatonin as an adjuvant in radiotherapy for radioprotection and radiosensitization
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits