JNK Signaling in the Control of the Tumor-Initiating Capacity Associated with Cancer Stem Cells.

Deregulation of c-Jun NH2-terminal kinase (JNK) signaling occurs frequently in a variety of human cancers, yet the exact role(s) of JNK deregulation in cancer cell biology remains to be fully elucidated. Our recent demonstration that the activity of JNK is required not only for self-renewal of glioma stem cells but also for their tumor initiation has, however, identified a new role for JNK in the control of the stemness and tumor-initiating capacity of cancer cells. Significantly, transient JNK inhibition was sufficient to cause sustained loss of the tumor-initiating capacity of glioma stem cells, suggesting that the phenotype of "lost tumor-initiating capacity" may be as stable as the differentiated state and that the tumor-initiating capacity might therefore be under the control of JNK through an epigenetic mechanism that also governs stemness and differentiation. Here, in this article, we review the role and mechanism of JNK in the control of this "stemness-associated tumor-initiating capacity" (STATIC), a new hypothetical concept we introduce in this review article. Since the idea of STATIC is essentially applicable to both cancer types that do and do not follow the cancer stem cell hypothesis, we also give consideration to the possible involvement of JNK-mediated control of STATIC in a wide range of human cancers in which JNK is aberrantly activated. Theoretically, successful targeting of STATIC through JNK could contribute to long-term control of cancer. Issues to be considered before clinical application of therapies targeting this JNK-STATIC axis are also discussed.