Top

Published in:

01-04-2011 | Preclinical study

Involvement of PKC delta (PKCδ) in the resistance against different doxorubicin analogs

Authors: María Ines Díaz Bessone, Damian E. Berardi, Paola B. Campodónico, Laura B. Todaro, Leonard Lothstein, Elisa D. Bal de Kier Joffé, Alejandro J. Urtreger

Published in: Breast Cancer Research and Treatment | Issue 3/2011

Abstract

Doxorubicin is an anti-tumor antibiotic widely used in the management of cancer patients. Its main mechanism of action involves the generation of DNA damage and the inhibition of topoisomerase II, promoting apoptosis. AD 198 is a novel doxorubicin analog devoid of DNA binding and topoisomerase II inhibitory capacities. It has been proposed that AD 198 induces apoptosis by activating protein kinase C delta (PKCδ); a PKC isoform described as growth inhibitory in a large number of cell types. We have previously demonstrated that PKCδ overexpression in NMuMG cells induced the opposite effect, promoting proliferation and cell survival. In this study, we found that PKCδ overexpression confers an enhanced cell death resistance against AD 198 cytotoxic effect and against AD 288, another doxorubicin analog that preserves its mechanism of action. These resistances involve PKCδ-mediated activation of two well-known survival pathways: Akt and NF-κB. While the resistance against AD 198 could be abrogated upon the inhibition of either Akt or NF-κB pathways, only NF-κB inhibition could revert the resistance to AD 288. Altogether, our results indicate that PKCδ increases cell death resistance against different apoptosis inductors, independently of their mechanism of action, through a differential modulation of Akt and NF-κB pathways. Our study contributes to a better understanding of the mechanisms involved in PKCδ-induced resistance and may greatly impact in the rationale design of isozyme-specific PKC modulators as therapeutic agents.

Roaten JB, Kazanietz MG, Sweatman TW et al (2001) Molecular models of N-benzyladriamycin-14-valerate (AD 198) in complex with the phorbol ester-binding C1b domain of protein kinase C-delta. J Med Chem 44:1028–1034PubMedCrossRef

Bilyeu JD, Panta GR, Cavin LG et al (2004) Circumvention of nuclear factor kappaB-induced chemoresistance by cytoplasmic-targeted anthracyclines. Mol Pharmacol 65:1038–1047PubMedCrossRef

Roaten JB, Kazanietz MG, Caloca MJ et al (2002) Interaction of the novel anthracycline antitumor agent N-benzyladriamycin-14-valerate with the C1-regulatory domain of protein kinase C: structural requirements, isoform specificity, and correlation with drug cytotoxicity. Mol Cancer Ther 1:483–492PubMed

Lothstein L, Rodrigues PJ, Sweatman TW et al (1998) Cytotoxicity and intracellular biotransformation of N-benzyladriamycin-14-valerate (AD 198) are modulated by changes in 14-O-acyl chain length. Anticancer Drugs 9:58–66PubMedCrossRef

Dekker LV, Parker PJ (1994) Protein kinase C—a question of specificity. Trends Biochem Sci 19:73–77PubMedCrossRef

Grossoni VC, Falbo KB, Kazanietz MG et al (2007) Protein kinase C delta enhances proliferation and survival of murine mammary cells. Mol Carcinog 46:381–390PubMedCrossRef

Mellor H, Parker PJ (1998) The extended protein kinase C superfamily. Biochem J 332(Pt 2):281–292PubMed

Newton AC (1997) Regulation of protein kinase C. Curr Opin Cell Biol 9:161–167PubMedCrossRef

Newton AC (1995) Protein kinase C: structure, function, and regulation. J Biol Chem 270:28495–28498PubMedCrossRef

10.

Brodie C, Blumberg PM (2003) Regulation of cell apoptosis by protein kinase c delta. Apoptosis 8:19–27PubMedCrossRef

11.

Kang Y, Park JS, Kim SH et al (2000) Overexpression of protein kinase C delta represses expression of proliferin in NIH3T3 cells that regulates cell proliferation. Mol Cell Biol Res Commun 4:181–187PubMedCrossRef

12.

Mischak H, Goodnight JA, Kolch W et al (1993) Overexpression of protein kinase C-delta and -epsilon in NIH 3T3 cells induces opposite effects on growth, morphology, anchorage dependence, and tumorigenicity. J Biol Chem 268:6090–6096PubMed

13.

Brodie C, Kuperstein I, Acs P et al (1998) Differential role of specific PKC isoforms in the proliferation of glial cells and the expression of the astrocytic markers GFAP and glutamine synthetase. Brain Res Mol Brain Res 56:108–117PubMedCrossRef

14.

Harrington EO, Loffler J, Nelson PR et al (1997) Enhancement of migration by protein kinase Calpha and inhibition of proliferation and cell cycle progression by protein kinase Cdelta in capillary endothelial cells. J Biol Chem 272:7390–7397PubMedCrossRef

15.

Vucenik I, Ramakrishna G, Tantivejkul K et al (2005) Inositol hexaphosphate (IP6) blocks proliferation of human breast cancer cells through a PKCdelta-dependent increase in p27Kip1 and decrease in retinoblastoma protein (pRb) phosphorylation. Breast Cancer Res Treat 91:35–45PubMedCrossRef

16.

Cerda SR, Bissonnette M, Scaglione-Sewell B et al (2001) PKC-delta inhibits anchorage-dependent and -independent growth, enhances differentiation, and increases apoptosis in CaCo-2 cells. Gastroenterology 120:1700–1712PubMedCrossRef

17.

Tanaka Y, Gavrielides MV, Mitsuuchi Y et al (2003) Protein kinase C promotes apoptosis in LNCaP prostate cancer cells through activation of p38 MAPK and inhibition of the Akt survival pathway. J Biol Chem 278:33753–33762PubMedCrossRef

18.

Kiley SC, Clark KJ, Duddy SK et al (1999) Increased protein kinase C delta in mammary tumor cells: relationship to transformation and metastatic progression. Oncogene 18:6748–6757PubMedCrossRef

19.

McCracken MA, Miraglia LJ, McKay RA et al (2003) Protein kinase C delta is a prosurvival factor in human breast tumor cell lines. Mol Cancer Ther 2:273–281PubMed

20.

Clark AS, West KA, Blumberg PM et al (2003) Altered protein kinase C (PKC) isoforms in non-small cell lung cancer cells: PKCdelta promotes cellular survival and chemotherapeutic resistance. Cancer Res 63:780–786PubMed

21.

Kim D, Chung J (2002) Akt: versatile mediator of cell survival and beyond. J Biochem Mol Biol 35:106–115PubMed

22.

Horbinski C, Chu CT (2005) Kinase signaling cascades in the mitochondrion: a matter of life or death. Free Radic Biol Med 38:2–11PubMedCrossRef

23.

Hsieh HL, Wang HH, Wu CY et al (2007) BK-induced COX-2 expression via PKC-delta-dependent activation of p42/p44 MAPK and NF-kappaB in astrocytes. Cell Signal 19:330–340PubMedCrossRef

24.

Satoh A, Gukovskaya AS, Nieto JM et al (2004) PKC-delta and -epsilon regulate NF-kappaB activation induced by cholecystokinin and TNF-alpha in pancreatic acinar cells. Am J Physiol Gastrointest Liver Physiol 287:G582–G591PubMedCrossRef

25.

Lu ZG, Liu H, Yamaguchi T et al (2009) Protein kinase Cdelta activates RelA/p65 and nuclear factor-kappaB signaling in response to tumor necrosis factor-alpha. Cancer Res 69:5927–5935PubMedCrossRef

26.

Minhajuddin M, Bijli KM, Fazal F et al (2009) Protein kinase C-delta and phosphatidylinositol 3-kinase/Akt activate mammalian target of rapamycin to modulate NF-kappaB activation and intercellular adhesion molecule-1 (ICAM-1) expression in endothelial cells. J Biol Chem 284:4052–4061PubMedCrossRef

27.

Naugler WE, Karin M (2008) NF-kappaB and cancer-identifying targets and mechanisms. Curr Opin Genet Dev 18:19–26PubMedCrossRef

28.

Van den Broecke C, Vleminckx K, De Bruyne G et al (1996) Morphotypic plasticity in vitro and in nude mice of epithelial mouse mammary cells (NMuMG) displaying an epithelioid (e) or a fibroblastic (f) morphotype in culture. Clin Exp Metastasis 14:282–296PubMed

29.

Mazzoni E, Adam A, Bal de Kier Joffe E et al (2003) Immortalized mammary epithelial cells overexpressing protein kinase C gamma acquire a malignant phenotype and become tumorigenic in vivo. Mol Cancer Res 1:776–787PubMed

30.

Urtreger AJ, Grossoni VC, Falbo KB et al (2005) Atypical protein kinase C-zeta modulates clonogenicity, motility, and secretion of proteolytic enzymes in murine mammary cells. Mol Carcinog 42:29–39PubMedCrossRef

31.

Owens RB (1974) Glandular epithelial cells from mice: a method for selective cultivation. J Natl Cancer Inst 52:1375–1378PubMed

32.

Basu A (2003) Involvement of protein kinase C-delta in DNA damage-induced apoptosis. J Cell Mol Med 7:341–350PubMedCrossRef

33.

Lothstein L, Savranskaya L, Barrett CM et al (2006) N-benzyladriamycin-14-valerate (AD 198) activates protein kinase C-delta holoenzyme to trigger mitochondrial depolarization and cytochrome c release independently of permeability transition pore opening and Ca2+ influx. Anticancer Drugs 17:495–502PubMedCrossRef

34.

Griner EM, Kazanietz MG (2007) Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer 7:281–294PubMedCrossRef

35.

Mauro LV, Grossoni VC, Urtreger AJ et al (2010) PKC delta (PKCd) promotes tumoral progression of human ductal pancreatic cancer. Pancreas 39:31–41CrossRef

36.

Basu A, Akkaraju GR (1999) Regulation of caspase activation and cis-diamminedichloroplatinum(II)-induced cell death by protein kinase C. Biochemistry 38:4245–4251

37.

Gopee NV, He Q, Sharma RP (2003) Fumonisin B1-induced apoptosis is associated with delayed inhibition of protein kinase C, nuclear factor-kappaB and tumor necrosis factor alpha in LLC-PK1 cells. Chem Biol Interact 146:131–145PubMedCrossRef

38.

Grossoni VC, Falbo KB, Mauro LV et al (2007) Protein kinase C delta inhibits the production of proteolytic enzymes in murine mammary cells. Clin Exp Metastasis 24:513–520PubMedCrossRef

39.

Barrett CM, Lewis FL, Roaten JB et al (2002) Novel extranuclear-targeted anthracyclines override the antiapoptotic functions of Bcl-2 and target protein kinase C pathways to induce apoptosis. Mol Cancer Ther 1:469–481PubMed

40.

Lothstein L, Israel MSweatman TW (2001) Anthracycline drug targeting: cytoplasmic versus nuclear—a fork in the road. Drug Resist Updat 4:169–177PubMedCrossRef

Title: Involvement of PKC delta (PKCδ) in the resistance against different doxorubicin analogs
Authors: María Ines Díaz Bessone
Damian E. Berardi
Paola B. Campodónico
Laura B. Todaro
Leonard Lothstein
Elisa D. Bal de Kier Joffé
Alejandro J. Urtreger
Publication date: 01-04-2011
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 3/2011
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-010-0956-2

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

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2011

Spectrum of BRCA1/2 point mutations and genomic rearrangements in high-risk breast/ovarian cancer Chilean families

Significant association between ABCB1 gene C3435T polymorphism and breast cancer risk

The effects of oncotype DX recurrence scores on chemotherapy utilization in a multi-institutional breast cancer cohort

Concurrent use of tamoxifen with CYP2D6 inhibitors and the risk of breast cancer recurrence

Association between mitogen-activated protein kinase kinase kinase 1 rs889312 polymorphism and breast cancer risk: evidence from 59,977 subjects

Polymorphisms of tumor necrosis factor-alpha and breast cancer risk: a meta-analysis

Keynote webinar | Spotlight on antibody–drug conjugates in cancer