Targeting JNK for therapeutic depletion of stem-like glioblastoma cells

Abstract

Control of the stem-like tumour cell population is considered key to realizing the long-term survival of patients with glioblastoma, one of the most devastating human malignancies. To date, possible therapeutic targets and targeting methods have been described, but none has yet proven to target stem-like glioblastoma cells in the brain to the extent necessary to provide a survival benefit. Here we show that targeting JNK in vivo, the activity of which is required for the maintenance of stem-like glioblastoma cells, via transient, systemic administration of a small-molecule JNK inhibitor depletes the self-renewing and tumour-initiating populations within established tumours, inhibits tumour formation by stem-like glioblastoma cells in the brain, and provide substantial survival benefit without evidence of adverse events. Our findings not only implicate JNK in the maintenance of stem-like glioblastoma cells but also demonstrate that JNK is a viable, clinically relevant therapeutic target in the control of stem-like glioblastoma cells.

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

“…By definition, STATIC is a type of tumor-initiating capacity regulated in close association with the stemness/differentiation of the cells most likely through an epigenetic mechanism (5). Although we need to admit that the A549 cells used in this study may not be typical bona fide CSCs since they failed to grow as non-adherent spheres in the serum-free, stem cell culture condition (data not shown), the results of the present study strongly suggest that the A549 cells analyzed in this study share with glioblastoma stem cells the core mechanism of tumor-initiating capacity, which we have just shown to be STATIC (5,6). This idea is quite in good agreement with our prediction/proposal that STATIC may not always be associated with the stemness of the cells, for instance, in such a case where the regulatory mechanism governing stemness is selectively disrupted downstream of the core mechanism of STATIC that orchestrates stemness and tumor-initiating capacity (5).…”

“…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).…”

“…Although SP600125 thus failed to control the growth of the entire bulk A549 tumors, it was nevertheless still possible that SP600125 selectively reduced the tumor-initiating cell population within the tumors, just as we demonstrated previously using glioblastoma xenografts (6). To explore this possibility, we next conducted serial transplantation experiments.…”

“…Most importantly, we demonstrated for the first time in our recent study that 'sustained' JNK activity is not only required for the prevention of differentiation and maintenance of the 'stem cell state' of glioblastoma CSCs but also for the maintenance of their 'tumor-initiating capacity'. Furthermore, we showed in the study that transient, short-term inhibition of JNK in vivo is sufficient to exert a long-lasting suppressive effect on the tumor-initiating capacity of glioblastoma cells, suggesting that JNK could make an excellent therapeutic target to achieve long-term control of glioblastoma, one of the deadliest of all human cancers (5,6). However, to date, it remains totally unknown whether such a role of JNK in the control of the stemness and/or the tumor-initiating capacity of tumor cells is unique to glioblastoma or is commonly shared by other human cancers.…”

“…Mouse studies. Mouse xenograft studies were carried out essentially as previously described (6,23). For subcutaneous implantation of A549 cells, cells were suspended in 200 µl of PBS and injected into the flank region of 5-to 7-week-old male BALB/cAJcl-nu/nu mice (Clea Japan, Inc.).…”