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DOI:10.1158/0008-5472.CAN-11-1982

JNK-Induced Apoptosis, Compensatory Growth, and Cancer Stem Cells
Fei Chen Cancer Res 2012;72:379-386. Published online January 16, 2012.

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DOI:10.1158/0008-5472.CAN-11-1982

Review

Cancer Research

JNK-Induced Apoptosis, Compensatory Growth, and Cancer Stem Cells
Fei Chen

Abstract
Overwhelming evidence suggests that c-jun-NH2-kinases (JNK) are a set of keystress-responsive kinases that mediate cell apoptosis, which is an important process for tumor suppression. However, JNKs have also been implicated in the malignant transformation and tumorigenesis of cells. This review attempts to reconcile these 2 contradictory functions of JNKs with recent discoveries on the role of JNKs in compensatory growth of neighboring cells and stem cells, which may providenew mechanistic understanding about the role of JNKs in the regulation of cancer stem cells and the pathogenesis of cancers. Cancer Res; 72(2); 379–86. Ó2012 AACR.

Introduction
In the past few years, a new concept in tumorigenesis, the cancer stem cell (CSC), has emerged (1). It is believed that CSCs are a population of rare cells that are capable of initiating and maintaining the tumor,differentiating into endothelial cells for tumor vascularization, and allowing the propagation and colonization of tumor cells at sites distant from the original tumor location. Similar to normal stem cells, CSCs retain the properties of self-renewal and multilineage differentiation. However, these cells distinguish themselves from normal stem cells by maintaining their malignant potentials, such as aloss of both the genomic integrity and epigenetic identity of the normal stem cells. An unsolved issue in CSC theory is whether CSCs are truly stem cells or if they are non–stem cells in which the self-renewal is activated by oncogenic mechanisms. The c-jun–NH2–kinases (JNK) are protein kinases involved in cellular stress response, apoptosis, and malignant transformation (2–4). They regulate a widespectrum of intracellular signaling pathways that converge to regulate both gene expression and the homeostasis of macromolecules, including mRNAs and proteins (5). In the human genome, 3 genetic loci encode JNK1, JNK2, and JNK3, each of which has 2 to 4 isoforms that result from the alternative splicing of the corresponding pre-mRNAs. Both JNK1 and JNK2 are ubiquitously expressed, whereas JNK3 isexpressed predominantly in the brain and, to a lesser extent, in the heart and testis (2, 4). JNKs have a welldocumented functional redundancy to phosphorylate their cognate and noncognate substrates, which include c-Jun, JunD, ATF2, polycomb repressive complex 1 (PRC1) subunit Bmi1 (6), Akt (7) FoxO4, PPARg1, c-Myc, p53, NFATc2, STATs (8), IRS-1,
Author's Affiliation: Department ofPharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan Corresponding Author: Fei Chen, Wayne State University, 259 Mack Avenue, Detroit, MI 48201. Phone: 313-577-9201; Fax: 313-577-2033; E-mail: fchen@wayne.edu doi: 10.1158/0008-5472.CAN-11-1982 Ó2012 American Association for Cancer Research.

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