Involvement of PKC delta (PKCδ) in the resistance against different doxorubicin analogs.
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.
Díaz Bessone
María Ines
MI
Research Area, Institute of Oncology Angel H. Roffo, University of Buenos Aires, Av. San Martín 5481, Buenos Aires C1417DTB, Argentina.
Berardi
Damian E
DE
Campodónico
Paola B
PB
Todaro
Laura B
LB
Lothstein
Leonard
L
Bal de Kier Joffé
Elisa D
ED
Urtreger
Alejandro J
AJ
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D015674:Mammary Neoplasms, Animal / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013347:Subcellular Fractions
D000903:Antibiotics, Antineoplastic; D016328:NF-kappa B; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta; D004250:DNA Topoisomerases, Type II