nach oben

Journal of Cancer Research and Clinical Oncology

Erschienen in:

31.08.2020 | Original Article – Cancer Research

Protein Kinase C Alpha (PKCα) overexpression leads to a better response to retinoid acid therapy through Retinoic Acid Receptor Beta (RARβ) activation in mammary cancer cells

verfasst von: María Inés Díaz Bessone, Damián Emilio Berardi, Stéfano Martín Cirigliano, Damián Ignacio Delbart, María Giselle Peters, Laura Beatriz Todaro, Alejandro Jorge Urtreger

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 12/2020

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Retinoids have proved to be effective for hematologic malignancies treatment but till nowadays, their use as single agent for the solid tumor’s management is still controversial. All-trans retinoic acid (ATRA), the main active metabolite of vitamin A, exerts non-genomic interactions with different members of the protein kinase C (PKC) family, recognized modulators of different tumor progression pathways. To determine whether a group of patients could become benefited employing a retinoid therapy, in this study we have evaluated whether PKCα expression (a poor prognosis marker in breast cancer) could sensitizes mammary cells to ATRA treatment.

Methods

PKCα overexpression was achieved by stable transfection and confirmed by western blot. Transfected PKC functionality was determined by nuclear translocation-induction and confocal microscopy. In vitro proliferation was evaluated by cell counting and cell cycle distribution was analyzed by flow cytometry. In vivo studies were performed to evaluate orthotopic tumor growth and experimental lung colonization. Retinoic acid response elements (RARE) and AP1 sites-dependent activity was studied by gene reporter assays and retinoic acid receptors (RARs) were measured by RT-qPCR.

Results

Our findings suggest that high PKCα levels improve the differentiation response to ATRA in a RAR signaling-dependent manner. Moreover, RARβ expression appears to be critical to induce ATRA sensitization, throughout AP1 trans-repression.

Conclusion

Here we propose that retinoids could lead a highly personalized anticancer treatment, bringing benefits to patients with aggressive breast tumors resulting from high PKCα expression but, an adequate expression of the RARβ receptor is required to ensure the effect on this process.

Nur mit Berechtigung zugänglich

Al Tanoury Z, Piskunov A, Rochette-Egly C (2013) Vitamin A and retinoid signaling: genomic and nongenomic effects. J Lipid Res 54:1761–1775. https://doi.org/10.1194/jlr.R030833CrossRefPubMedPubMedCentral

Ali S, Al-Sukhun S, El-Rayes BF, Sarkar FH, Heilbrun LK, Philip PA (2009) Protein kinases C isozymes are differentially expressed in human breast carcinomas. Life Sci 84:766–771. https://doi.org/10.1016/j.lfs.2009.03.007CrossRefPubMed

Berardi DE, Bessone MI, Motter A, de Kier B, Joffe ED, Urtreger AJ, Todaro LB (2015) Involvement of protein kinase C alpha and delta activities on the induction of the retinoic acid system in mammary cancer cells. Mol Carcinog 54:1110–1121. https://doi.org/10.1002/mc.22181CrossRefPubMed

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA. Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492CrossRef

Cameron AJ, Procyk KJ, Leitges M, Parker PJ (2008) PKC alpha protein but not kinase activity is critical for glioma cell proliferation and survival. Int J Cancer 123:769–779. https://doi.org/10.1002/ijc.23560CrossRefPubMed

Castaigne S, Chomienne C, Daniel MT, Ballerini P, Berger R, Fenaux P, Degos L (1990) All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I Clin Results Blood 76:1704–1709

Chen N, Napoli JL (2008) All-trans-retinoic acid stimulates translation and induces spine formation in hippocampal neurons through a membrane-associated RARalpha. FASEB J 22:236–245. https://doi.org/10.1096/fj.07-8739comCrossRefPubMed

Cho Y, Tighe AP, Talmage DA (1997) Retinoic acid induced growth arrest of human breast carcinoma cells requires protein kinase C alpha expression and activity. J Cell Physiol 172:306–313. https://doi.org/10.1002/(SICI)1097-4652(199709)172:3<306:AID-JCP4>3.0.CO;2-SCrossRefPubMed

Decensi A et al (2009) Randomized double-blind 2 x 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in high-risk premenopausal women. J Clin Oncol 27:3749–3756. https://doi.org/10.1200/JCO.2008.19.3797CrossRefPubMedPubMedCentral

Dedieu S, Lefebvre P (2006) Retinoids interfere with the AP1 signalling pathway in human breast cancer cells. Cell Signal 18:889–898. https://doi.org/10.1016/j.cellsig.2005.08.001CrossRefPubMed

Dekker LV, Parker PJ (1994) Protein kinase C–a question of specificity. Trends Biochem Sci 19:73–77. https://doi.org/10.1016/0968-0004(94)90038-8CrossRefPubMed

Delmotte MH, Tahayato A, Formstecher P, Lefebvre P (1999) Serine 157, a retinoic acid receptor alpha residue phosphorylated by protein kinase C in vitro, is involved in RXR.RARalpha heterodimerization and transcriptional activity. J Biol Chem 274:38225–38231. https://doi.org/10.1074/jbc.274.53.38225CrossRefPubMed

Desai DS, Hirai S, Karnes WE Jr, Niles RM, Ohno S (1999) Cloning and characterization of the murine PKC alpha promoter: identification of a retinoic acid response element. Biochem Biophys Res Commun 263:28–34. https://doi.org/10.1006/bbrc.1999.1307CrossRefPubMed

Dobrotkova V, Chlapek P, Mazanek P, Sterba J, Veselska R (2018) Traffic lights for retinoids in oncology: molecular markers of retinoid resistance and sensitivity and their use in the management of cancer differentiation therapy. BMC Cancer 18:1059. https://doi.org/10.1186/s12885-018-4966-5CrossRefPubMedPubMedCentral

Flamini MI, Gauna GV, Sottile ML, Nadin BS, Sanchez AM, Vargas-Roig LM (2014) Retinoic acid reduces migration of human breast cancer cells: role of retinoic acid receptor beta. J Cell Mol Med 18:1113–1123. https://doi.org/10.1111/jcmm.12256CrossRefPubMedPubMedCentral

Gao T et al (2013) The association of retinoic acid receptor beta2(RARbeta2) methylation status and prostate cancer risk: a systematic review and meta-analysis. PLoS ONE 8:e62950. https://doi.org/10.1371/journal.pone.0062950CrossRefPubMedPubMedCentral

Garattini E et al (2014) Retinoids and breast cancer: from basic studies to the clinic and back again. Cancer Treat Rev 40:739–749. https://doi.org/10.1016/j.ctrv.2014.01.001CrossRefPubMed

Garg R, Benedetti LG, Abera MB, Wang H, Abba M, Kazanietz MG (2014) Protein kinase C and cancer: what we know and what we do not. Oncogene 33:5225–5237. https://doi.org/10.1038/onc.2013.524CrossRefPubMed

Gentilini LD et al (2017) Stable and high expression of Galectin-8 tightly controls metastatic progression of prostate cancer. Oncotarget 8:44654–44668. https://doi.org/10.18632/oncotarget.17963CrossRefPubMedPubMedCentral

Griner EM, Kazanietz MG (2007) Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer 7:281–294. https://doi.org/10.1038/nrc2110CrossRefPubMed

Grossoni VC, Todaro LB, Kazanietz MG, de Kier Joffe ED, Urtreger AJ (2009) Opposite effects of protein kinase C beta1 (PKCbeta1) and PKCepsilon in the metastatic potential of a breast cancer murine model. Breast Cancer Res Treat 118:469–480. https://doi.org/10.1007/s10549-008-0299-4CrossRefPubMed

Gudas LJ (1994) Retinoids and vertebrate development. J Biol Chem 269:15399–15402PubMed

Gupta P et al (2008) Retinoic acid-stimulated sequential phosphorylation, PML recruitment, and SUMOylation of nuclear receptor TR2 to suppress Oct4 expression. Proc Natl Acad Sci USA 105:11424–11429. https://doi.org/10.1073/pnas.0710561105CrossRefPubMed

Haughian JM, Reno EM, Thorne AM, Bradford AP (2009) Protein kinase C alpha-dependent signaling mediates endometrial cancer cell growth and tumorigenesis. Int J Cancer 125:2556–2564. https://doi.org/10.1002/ijc.24633CrossRefPubMedPubMedCentral

Kambhampati S et al (2003) Activation of protein kinase C delta by all-trans-retinoic acid. J Biol Chem 278:32544–32551. https://doi.org/10.1074/jbc.M301523200CrossRefPubMed

Karamouzis MV, Sotiropoulou-Bonikou G, Vandoros G, Varakis I, Papavassiliou AG (2004) Differential expression of retinoic acid receptor beta (RARbeta) and the AP-1 transcription factor in normal, premalignant and malignant human laryngeal tissues. Eur J Cancer 40:761–773. https://doi.org/10.1016/j.ejca.2003.12.002CrossRefPubMed

Kong C et al (2005) Role of protein kinase C-alpha in superficial bladder carcinoma recurrence. Urology 65:1228–1232. https://doi.org/10.1016/j.urology.2005.01.007CrossRefPubMed

Lin F, Xiao D, Kolluri SK, Zhang X (2000) Unique anti-activator protein-1 activity of retinoic acid receptor beta. Cancer Res 60:3271–3280PubMed

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Method Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262(1262 S1046-2023(01)91262-9 [pii])CrossRefPubMed

Newton AC (1995) Protein kinase C: structure, function, and regulation. J Biol Chem 270:28495–28498. https://doi.org/10.1074/jbc.270.48.28495CrossRefPubMed

Newton AC (2018) Protein kinase C: perfectly balanced. Crit Rev Biochem Mol Biol 53:208–230. https://doi.org/10.1080/10409238.2018.1442408CrossRefPubMedPubMedCentral

Nishizuka Y (1995) Protein kinase C and lipid signaling for sustained cellular responses. FASEB J 9:484–496CrossRef

Ochoa WF, Torrecillas A, Fita I, Verdaguer N, Corbalan-Garcia S, Gomez-Fernandez JC (2003) Retinoic acid binds to the C2-domain of protein kinase C(alpha). Biochemistry 42:8774–8779. https://doi.org/10.1021/bi034713gCrossRefPubMed

Picard E et al (1999) Expression of retinoid receptor genes and proteins in non-small-cell lung cancer. J Natl Cancer Inst 91:1059–1066. https://doi.org/10.1093/jnci/91.12.1059CrossRefPubMed

Radominska-Pandya A, Chen G, Czernik PJ, Little JM, Samokyszyn VM, Carter CA, Nowak G (2000) Direct interaction of all-trans-retinoic acid with protein kinase C (PKC) Implications for PKC signaling and cancer therapy. J Biol Chem 275:22324–22330. https://doi.org/10.1074/jbc.M907722199CrossRefPubMed

Shaulian E (2010) AP-1–The Jun proteins: oncogenes or tumor suppressors in disguise? Cell Signal 22:894–899. https://doi.org/10.1016/j.cellsig.2009.12.008CrossRefPubMed

Simon D et al (2002) Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study. Eur J Nucl Med Mol Imaging 29:775–782. https://doi.org/10.1007/s00259-001-0737-6CrossRefPubMed

Stefanska B, Rudnicka K, Bednarek A, Fabianowska-Majewska K (2010) Hypomethylation and induction of retinoic acid receptor beta 2 by concurrent action of adenosine analogues and natural compounds in breast cancer cells. Eur J Pharmacol 638:47–53. https://doi.org/10.1016/j.ejphar.2010.04.032CrossRefPubMed

Tallman MS, Altman JK (2009) How I treat acute promyelocytic leukemia. Blood 114:5126–5135. https://doi.org/10.1182/blood-2009-07-216457CrossRefPubMed

Tang XH, Gudas LJ (2011) Retinoids, retinoic acid receptors, and cancer. Annu Rev Pathol 6:345–364. https://doi.org/10.1146/annurev-pathol-011110-130303CrossRefPubMed

Tighe AP, Talmage DA (2004) Retinoids arrest breast cancer cell proliferation: retinoic acid selectively reduces the duration of receptor tyrosine kinase signaling. Exp Cell Res 301:147–157. https://doi.org/10.1016/j.yexcr.2004.07.008CrossRefPubMedPubMedCentral

Tonetti DA, Chisamore MJ, Grdina W, Schurz H, Jordan VC (2000) Stable transfection of protein kinase C alpha cDNA in hormone-dependent breast cancer cell lines. Br J Cancer 83:782–791. https://doi.org/10.1054/bjoc.2000.1326CrossRefPubMedPubMedCentral

Urtreger A, Ladeda V, Puricelli L, Rivelli A, Vidal M, Delustig E, Joffe E (1997) Modulation of fibronectin expression and proteolytic activity associated with the invasive and metastatic phenotype in two new murine mammary tumor cell lines. Int J Oncol 11:489–496. https://doi.org/10.3892/ijo.11.3.489CrossRefPubMed

Urtreger AJ, Kazanietz MG, de Kier B, Joffe ED (2012) Contribution of individual PKC isoforms to breast cancer progression. IUBMB Life 64:18–26. https://doi.org/10.1002/iub.574CrossRefPubMed

Wang Y et al (2003) Hypermethylation-associated inactivation of retinoic acid receptor beta in human esophageal squamous cell carcinoma. Clin Cancer Res 9:5257–5263PubMed

Widschwendter M et al (2000) Methylation and silencing of the retinoic acid receptor-beta2 gene in breast cancer. J Natl Cancer Inst 92:826–832. https://doi.org/10.1093/jnci/92.10.826CrossRefPubMed

Wu B, Zhou H, Hu L, Mu Y, Wu Y (2013) Involvement of PKCalpha activation in TF/VIIa/PAR2-induced proliferation, migration, and survival of colon cancer cell SW620. Tumour Biol 34:837–846. https://doi.org/10.1007/s13277-012-0614-xCrossRefPubMed

Wu MJ, Kim MR, Chen YS, Yang JY, Chang CJ (2017) Retinoic acid directs breast cancer cell state changes through regulation of TET2-PKCzeta pathway. Oncogene 36:3193–3206. https://doi.org/10.1038/onc.2016.467CrossRefPubMedPubMedCentral

Yang L, Kim HT, Munoz-Medellin D, Reddy P, Brown PH (1997) Induction of retinoid resistance in breast cancer cells by overexpression of cJun. Cancer Res 57:4652–4661PubMed

Youssef EM et al (2004) Hypermethylation of the retinoic acid receptor-beta(2) gene in head and neck carcinogenesis. Clin Cancer Res 10:1733–1742. https://doi.org/10.1158/1078-0432.ccr-0989-3CrossRefPubMed

Zanardi S, Serrano D, Argusti A, Barile M, Puntoni M, Decensi A (2006) Clinical trials with retinoids for breast cancer chemoprevention. Endocr Relat Cancer 13:51–68. https://doi.org/10.1677/erc.1.00938CrossRefPubMed

Titel: Protein Kinase C Alpha (PKCα) overexpression leads to a better response to retinoid acid therapy through Retinoic Acid Receptor Beta (RARβ) activation in mammary cancer cells
verfasst von: María Inés Díaz Bessone
Damián Emilio Berardi
Stéfano Martín Cirigliano
Damián Ignacio Delbart
María Giselle Peters
Laura Beatriz Todaro
Alejandro Jorge Urtreger
Publikationsdatum: 31.08.2020
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 12/2020
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-020-03368-7

Neu im Fachgebiet Onkologie

Umsetzung der POMGAT-Leitlinie läuft

03.05.2024 DCK 2024 Kongressbericht

Seit November 2023 gibt es evidenzbasierte Empfehlungen zum perioperativen Management bei gastrointestinalen Tumoren (POMGAT) auf S3-Niveau. Vieles wird schon entsprechend der Empfehlungen durchgeführt. Wo es im Alltag noch hapert, zeigt eine Umfrage in einem Klinikverbund.

Springer Medizin

Protein Kinase C Alpha (PKCα) overexpression leads to a better response to retinoid acid therapy through Retinoic Acid Receptor Beta (RARβ) activation in mammary cancer cells