c-Jun N-terminal kinase has a pivotal role in the maintenance of self-renewal and tumorigenicity in glioma stem-like cells

Abstract

Uncovering the mechanisms that govern the maintenance of stem-like cancer cells is critical for developing therapeutic strategies for targeting these cells. Constitutive activation of c-Jun N-terminal kinase (JNK) has been reported in gliomas and correlates with histological grade. Here, we found that JNK signaling is crucial for the maintenance of 'stemness' in glioma cells. Sphere-cultured glioma cells showed more phosphorylation of JNK compared with serum-containing monolayer cultures. Importantly, blockade of JNK signaling with SP600125 or small interfering RNAs targeting JNK1 or JNK2 significantly reduced the CD133 þ /Nestin þ population and suppressed sphere formation, colony formation in soft agar, and expression of stem cell markers in sphere-cultured glioma cells. Intriguingly, sphere-cultured glioma cells exhibited enhanced expression of Notch-2, but not Notch-1, -3 or -4, and JNK inhibition almost completely abrogated this increase. Blocking the phosphoinoside 3-kinase (PI3K)/Akt pathway with LY294002 or si-Akt also suppressed the self-renewal of sphere-cultured glioma cells. PI3K, but not Akt, had a role as an upstream kinase in JNK1/2 activation. In addition, treatment with si-JNK greatly increased etoposideand ionizing radiation (IR)-induced cell death in glioma spheres. Consistent with glioma cell lines, glioma stem-like cells isolated from primary patient glioma cells also had a higher activity of JNK and Notch-2 expression. Importantly, inhibition of JNK2 led to a decrease of Notch-2 expression and suppressed the CD133 þ /Nestin þ cell population in patient-derived primary glioma cells. Finally, downregulation of JNK2 almost completely suppressed intracranial tumor formation by glioma cells in nude mice. Taken together, these data demonstrate that JNK signaling is crucial for the maintenance of self-renewal and tumorigenicity of glioma stem-like cells and drug/IR resistance, and can be considered a promising target for eliminating stem-like cancer cells in gliomas.

Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells

“…On the other hand, accumulating evidence has now come to support the emerging idea that JNK also plays significant roles in the 'promotion' of tumor growth (3)(4)(5). Only recently, an essential role of JNK in the maintenance of the tumor-initiating capacity of glioblastoma stem cells has been documented and added as one of such 'pro-tumor' roles of JNK (6,7). In line with such roles of JNK, aberrant activation of JNK has been increasingly observed in human cancers (3)(4)(5).…”

Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma

“…11 Although JNK1 and JNK2 have been considered redundant kinases, there is evidence for distinct or even opposing functions of JNK1 and JNK2 in tumorigenesis. [12][13][14][15] Thus, it has been reported that JNK2, but not JNK1, is essential for growth of various human cancer cells including lung, 16,17 glioblastoma, 18,19 prostate and skin. [20][21][22] In contrast, a recent study reported that JNK1 is essential for liver carcinogenesis, while JNK2 appears to be dispensable.…”

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

“…Also, the combined actions of JNK1 and JNK2 have been implicated in the proliferation of glioma cells (197). The underlying causes for these different outcomes remain unresolved, but some researchers have proposed a regeneration-based model as the basis of enhanced tumorigenesis, especially in the liver (198).…”