title: The selective inhibition of nuclear PKCζ restores the effectiveness of chemotherapeutic agents in chemoresistant cells.
abstract: The atypical protein kinase C (PKC) isoform zeta (PKCζ) has been implicated in the intracellular transduction of mitogenic and apoptotic signals by acting on different signaling pathways. The key role of these processes in tumorigenesis suggests a possible involvement of PKCζ in this event. PKCζ is activated by cytotoxic treatments, inhibits apoptotic cell death and reduces the sensitivity of cancer cells to chemotherapeutic agents. Here, using pharmacological and DNA recombinant approaches, we show that oxidative stress triggers nuclear translocation of PKCζ and induces resistance to apoptotic agents. Accordingly, chemoresistant cells show accumulation of PKCζ within the nucleus, and a nuclear-targeted PKCζ transfected in tumor cells decreases sensitivity to apoptosis. We thus developed a novel recombinant protein capable of selectively inhibiting the nuclear fraction of PKCζ that restored the susceptibility to apoptosis in cells in which PKCζ was enriched in the nuclear fraction, including chemoresistant cells. These findings establish the importance of PKCζ as a possible target to increase the effectiveness of anticancer therapies and highlight potential sites of intervention.
authors.affiliation: Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI), Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rimessi
authors.forename: Erika
authors.initials: E
authors.lastname: Zecchini
authors.forename: Roberta
authors.initials: R
authors.lastname: Siviero
authors.forename: Carlotta
authors.initials: C
authors.lastname: Giorgi
authors.forename: Sara
authors.initials: S
authors.lastname: Leo
authors.forename: Rosario
authors.initials: R
authors.lastname: Rizzuto
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
mesh_terms: D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D018384:Oxidative Stress; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection; D000099221:Protein Kinase C zeta
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D011493:Protein Kinase C; D017382:Reactive Oxygen Species; D000099221:Protein Kinase C zeta