Protein Kinase C (PKC) Isozymes As Diagnostic and Prognostic Biomarkers and Therapeutic Targets for Cancer

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2022 Nov 11

PMID 36358843

Authors

Takahito Kawano

Junichi Inokuchi

Masatoshi Eto

Masaharu Murata

Jeong-Hun Kang

Affiliations

Soon will be listed here.

Abstract

Protein kinase C (PKC) is a large family of calcium- and phospholipid-dependent serine/threonine kinases that consists of at least 11 isozymes. Based on their structural characteristics and mode of activation, the PKC family is classified into three subfamilies: conventional or classic (cPKCs; α, βI, βII, and γ), novel or non-classic (nPKCs; δ, ε, η, and θ), and atypical (aPKCs; ζ, ι, and λ) (PKCλ is the mouse homolog of PKCι) PKC isozymes. PKC isozymes play important roles in proliferation, differentiation, survival, migration, invasion, apoptosis, and anticancer drug resistance in cancer cells. Several studies have shown a positive relationship between PKC isozymes and poor disease-free survival, poor survival following anticancer drug treatment, and increased recurrence. Furthermore, a higher level of PKC activation has been reported in cancer tissues compared to that in normal tissues. These data suggest that PKC isozymes represent potential diagnostic and prognostic biomarkers and therapeutic targets for cancer. This review summarizes the current knowledge and discusses the potential of PKC isozymes as biomarkers in the diagnosis, prognosis, and treatment of cancers.

Citing Articles

Imaging the Raf-MEK-ERK Signaling Cascade in Living Cells.

Shin Y, Cho M, Hwang J, Myung K, Kweon H, Lee Z Int J Mol Sci. 2024; 25(19).

PMID: 39408915 PMC: 11477372. DOI: 10.3390/ijms251910587.

An Ingenane-Type Diterpene from Promoted Cell Apoptosis and Macrophage Polarization via the Regulation of PKC Signaling Pathways.

Feng X, Wang L, Pu L, Li J, Li H, Liu D Int J Mol Sci. 2024; 25(18).

PMID: 39337608 PMC: 11432454. DOI: 10.3390/ijms251810123.

Prenatal opioid exposure significantly impacts placental protein kinase C (PKC) and drug transporters, leading to drug resistance and neonatal opioid withdrawal syndrome.

Radhakrishna U, Radhakrishnan R, Uppala L, Muvvala S, Prajapati J, Rawal R Front Neurosci. 2024; 18:1442915.

PMID: 39238930 PMC: 11376091. DOI: 10.3389/fnins.2024.1442915.

Glutathione-Dependent Pathways in Cancer Cells.

Kalinina E Int J Mol Sci. 2024; 25(15).

PMID: 39125992 PMC: 11312684. DOI: 10.3390/ijms25158423.

Anti-Neuroinflammatory Effects of a Macrocyclic Peptide-Peptoid Hybrid in Lipopolysaccharide-Stimulated BV2 Microglial Cells.

Sun L, Saliba S, Apweiler M, Akmermer K, Herlan C, Grathwol C Int J Mol Sci. 2024; 25(8).

PMID: 38674048 PMC: 11049839. DOI: 10.3390/ijms25084462.

References

Tang C, Wang Y, Zhang L, Wang J, Wang W, Han X . Identification of novel LncRNA targeting Smad2/PKCα signal pathway to negatively regulate malignant progression of glioblastoma. J Cell Physiol. 2019; 235(4):3835-3848. PMC: 6972644. DOI: 10.1002/jcp.29278. View

Sharif T, Sharif M . Overexpression of protein kinase C epsilon in astroglial brain tumor derived cell lines and primary tumor samples. Int J Oncol. 1999; 15(2):237-43. View

Newton A . Protein kinase C: perfectly balanced. Crit Rev Biochem Mol Biol. 2018; 53(2):208-230. PMC: 5901981. DOI: 10.1080/10409238.2018.1442408. View

Piperno-Neumann S, Larkin J, Carvajal R, Luke J, Schwartz G, Hodi F . Genomic Profiling of Metastatic Uveal Melanoma and Clinical Results of a Phase I Study of the Protein Kinase C Inhibitor AEB071. Mol Cancer Ther. 2020; 19(4):1031-1039. DOI: 10.1158/1535-7163.MCT-19-0098. View

zum Buschenfelde C, Wagner M, Lutzny G, Oelsner M, Feuerstacke Y, Decker T . Recruitment of PKC-betaII to lipid rafts mediates apoptosis-resistance in chronic lymphocytic leukemia expressing ZAP-70. Leukemia. 2009; 24(1):141-52. DOI: 10.1038/leu.2009.216. View

Cheng Y, Zhu Y, Xu W, Xu J, Yang M, Chen P . PKCα in colon cancer cells promotes M1 macrophage polarization via MKK3/6-P38 MAPK pathway. Mol Carcinog. 2018; 57(8):1017-1029. DOI: 10.1002/mc.22822. View

Huang B, Cao K, Li X, Guo S, Mao X, Wang Z . The expression and role of protein kinase C (PKC) epsilon in clear cell renal cell carcinoma. J Exp Clin Cancer Res. 2011; 30:88. PMC: 3193168. DOI: 10.1186/1756-9966-30-88. View

Brenner W, Greber I, Gudejko-Thiel J, Beitz S, Schneider E, Walenta S . Migration of renal carcinoma cells is dependent on protein kinase Cdelta via beta1 integrin and focal adhesion kinase. Int J Oncol. 2008; 32(5):1125-31. View

Huang H, Wu H, Chu P, Lai I, Huang P, Kulp S . Role of integrin-linked kinase in regulating the protein stability of the MUC1-C oncoprotein in pancreatic cancer cells. Oncogenesis. 2017; 6(7):e359. PMC: 5541713. DOI: 10.1038/oncsis.2017.61. View

10.

Weichert W, Gekeler V, Denkert C, Dietel M, Hauptmann S . Protein kinase C isoform expression in ovarian carcinoma correlates with indicators of poor prognosis. Int J Oncol. 2003; 23(3):633-9. View

11.

Hans C, Weisenburger D, Greiner T, Chan W, Aoun P, Cochran G . Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma. Mod Pathol. 2005; 18(10):1377-84. DOI: 10.1038/modpathol.3800434. View

12.

Loi T, Dai P, Carlin S, Melo J, Ma D . Pro-survival role of protein kinase C epsilon in Philadelphia chromosome positive acute leukemia. Leuk Lymphoma. 2015; 57(2):411-418. DOI: 10.3109/10428194.2015.1043545. View

13.

Nayak R, Hegde S, Althoff M, Wellendorf A, Mohmoud F, Perentesis J . The signaling axis atypical protein kinase C λ/ι-Satb2 mediates leukemic transformation of B-cell progenitors. Nat Commun. 2019; 10(1):46. PMC: 6320370. DOI: 10.1038/s41467-018-07846-y. View

14.

Garg R, Cooke M, Benavides F, Abba M, Cicchini M, Feldser D . PKC Is Required for KRAS-Driven Lung Tumorigenesis. Cancer Res. 2020; 80(23):5166-5173. PMC: 7962984. DOI: 10.1158/0008-5472.CAN-20-1300. View

15.

Pal D, Outram S, Basu A . Upregulation of PKCη by PKCε and PDK1 involves two distinct mechanisms and promotes breast cancer cell survival. Biochim Biophys Acta. 2013; 1830(8):4040-5. PMC: 3697430. DOI: 10.1016/j.bbagen.2013.03.028. View

16.

Tsai J, Redei D, Hohmann J, Wu C . 12-Deoxyphorbol Esters Induce Growth Arrest and Apoptosis in Human Lung Cancer A549 Cells Via Activation of PKC-δ/PKD/ERK Signaling Pathway. Int J Mol Sci. 2020; 21(20). PMC: 7589005. DOI: 10.3390/ijms21207579. View

17.

Yamada K, Oikawa T, Kizawa R, Motohashi S, Yoshida S, Kumamoto T . Unconventional Secretion of PKCδ Exerts Tumorigenic Function via Stimulation of ERK1/2 Signaling in Liver Cancer. Cancer Res. 2020; 81(2):414-425. DOI: 10.1158/0008-5472.CAN-20-2009. View

18.

Tsai J, Tsai M, Su W, Chen Y, Wu T, Hsieh Y . Expression of protein kinase C alpha in biopsies and surgical specimens of human hepatocellular carcinoma. Chin J Physiol. 2005; 48(3):139-43. View

19.

Sedivy R, Marian B . Protein kinase C tissue localization in human colonic tumors suggests a role for adenoma growth control. Gastroenterology. 1996; 110(6):1753-9. DOI: 10.1053/gast.1996.v110.pm8964400. View

20.

Wu L, Li Y, Xu X, Zhu X . Circular RNA circ-PRKCI promotes cell proliferation and invasion by binding to microRNA-545 in gastric cancer. Eur Rev Med Pharmacol Sci. 2019; 23(21):9418-9426. DOI: 10.26355/eurrev_201911_19435. View