Atypical Protein Kinase C iota as a human oncogene and therapeutic target

TY - JOUR

T1 - Atypical Protein Kinase C iota as a human oncogene and therapeutic target

AU - Parker, Peter J.

AU - Justilien, Verline

AU - Riou, Philippe

AU - Linch, Mark

AU - Fields, Alan P.

PY - 2014/3/1

Y1 - 2014/3/1

N2 - Protein kinase inhibitors represent a major class of targeted therapeutics that has made a positive impact on treatment of cancer and other disease indications. Among the promising kinase targets for further therapeutic development are members of the Protein Kinase C (PKC) family. The PKCs are central components of many signaling pathways that regulate diverse cellular functions including proliferation, cell cycle, differentiation, survival, cell migration, and polarity. Genetic manipulation of individual PKC isozymes has demonstrated that they often fulfill distinct, nonredundant cellular functions. Participation of PKC members in different intracellular signaling pathways reflects responses to varying extracellular stimuli, intracellular localization, tissue distribution, phosphorylation status, and intermolecular interactions. PKC activity, localization, phosphorylation, and/or expression are often altered in human tumors, and PKC isozymes have been implicated in various aspects of transformation, including uncontrolled proliferation, migration, invasion, metastasis, angiogenesis, and resistance to apoptosis. Despite the strong relationship between PKC isozymes and cancer, to date only atypical PKCiota has been shown to function as a bona fide oncogene, and as such is a particularly attractive therapeutic target for cancer treatment. In this review, we discuss the role of PKCiota in transformation and describe mechanism-based approaches to therapeutically target oncogenic PKCiota signaling in cancer.

AB - Protein kinase inhibitors represent a major class of targeted therapeutics that has made a positive impact on treatment of cancer and other disease indications. Among the promising kinase targets for further therapeutic development are members of the Protein Kinase C (PKC) family. The PKCs are central components of many signaling pathways that regulate diverse cellular functions including proliferation, cell cycle, differentiation, survival, cell migration, and polarity. Genetic manipulation of individual PKC isozymes has demonstrated that they often fulfill distinct, nonredundant cellular functions. Participation of PKC members in different intracellular signaling pathways reflects responses to varying extracellular stimuli, intracellular localization, tissue distribution, phosphorylation status, and intermolecular interactions. PKC activity, localization, phosphorylation, and/or expression are often altered in human tumors, and PKC isozymes have been implicated in various aspects of transformation, including uncontrolled proliferation, migration, invasion, metastasis, angiogenesis, and resistance to apoptosis. Despite the strong relationship between PKC isozymes and cancer, to date only atypical PKCiota has been shown to function as a bona fide oncogene, and as such is a particularly attractive therapeutic target for cancer treatment. In this review, we discuss the role of PKCiota in transformation and describe mechanism-based approaches to therapeutically target oncogenic PKCiota signaling in cancer.

KW - Atypical Protein Kinase C iota

KW - Cellular transformation

KW - Phox-Bem1 (PB1) domain

KW - Mechanism-based therapeutics

KW - Oncogenic signaling

KW - DRUG-INDUCED APOPTOSIS

KW - PROSTATE-CANCER CELLS

KW - NERVE GROWTH-FACTOR

KW - LUNG-CANCER

KW - PKC-IOTA

KW - TRANSFORMED GROWTH

KW - URSOLIC ACID

KW - IN-VIVO

KW - MESENCHYMAL TRANSITION

KW - EXPRESSION PATTERNS

U2 - 10.1016/j.bcp.2013.10.023

DO - 10.1016/j.bcp.2013.10.023

M3 - Article

SN - 0006-2952

VL - 88

SP - 1

EP - 11

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

IS - 1

M1 - N/A

ER -