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Targeting JNK for therapeutic depletion of stem-like glioblastoma cells.

Matsuda K, Sato A, Okada M, Shibuya K, Seino S, Suzuki K, Watanabe E, Narita Y, Shibui S, Kayama T, Kitanaka C - Sci Rep (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, 990-9585, Japan.

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.

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Related in: MedlinePlus

Differential activation of the JNK signalling pathway in self-renewing and differentiated stem-like glioblastoma cells.(a–b) Self-renewing (maintained under the monolayer stem cell culture condition; SR) and differentiated (cultured under the differentiation-inducing condition for 1 week; Diff) stem-like glioblastoma cells were subjected to immunoblot analysis to examine the activation/phosphorylation status of the JNK signalling pathway (a) and that of AKT, ERK, and p38 (b).
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f1: Differential activation of the JNK signalling pathway in self-renewing and differentiated stem-like glioblastoma cells.(a–b) Self-renewing (maintained under the monolayer stem cell culture condition; SR) and differentiated (cultured under the differentiation-inducing condition for 1 week; Diff) stem-like glioblastoma cells were subjected to immunoblot analysis to examine the activation/phosphorylation status of the JNK signalling pathway (a) and that of AKT, ERK, and p38 (b).

Mentions: To identify candidate regulators of the stem-like properties (i.e., the capacity to self-renew and to undergo multi-lineage differentiation, see Supplementary Fig. 1 for characterization of the stem-like glioblastoma cells used in this study) of stem-like glioblastoma cells, we searched for molecules differentially expressed and/or activated in self-renewing and differentiated stem-like glioblastoma cells. We found that, compared to their differentiated counterparts, self-renewing stem-like glioblastoma cells have elevated levels of JNK phosphorylation at the activating phosphorylation sites. We also found that the increased JNK phosphorylation is accompanied by increased c-Jun phosphorylation at the cognate JNK phosphorylation site, indicating increased JNK pathway activation in self-renewing cells (Fig. 1a). Notably, whereas the differential activation status of other signalling pathways implicated in glioblastoma biology and of related MAPK superfamily members1116 was inconsistent and varied depending on the cell line tested (Fig. 1b), the JNK pathway was consistently activated in self-renewing cells relative to differentiated cells in all the stem-like glioblastoma cell lines tested including those directly derived from glioblastoma patients (patient-derived stem-like glioblastoma cells) as well as those established from conventional, serum-cultured cell lines (Fig. 1a).


Targeting JNK for therapeutic depletion of stem-like glioblastoma cells.

Matsuda K, Sato A, Okada M, Shibuya K, Seino S, Suzuki K, Watanabe E, Narita Y, Shibui S, Kayama T, Kitanaka C - Sci Rep (2012)

Differential activation of the JNK signalling pathway in self-renewing and differentiated stem-like glioblastoma cells.(a–b) Self-renewing (maintained under the monolayer stem cell culture condition; SR) and differentiated (cultured under the differentiation-inducing condition for 1 week; Diff) stem-like glioblastoma cells were subjected to immunoblot analysis to examine the activation/phosphorylation status of the JNK signalling pathway (a) and that of AKT, ERK, and p38 (b).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3400080&req=5

f1: Differential activation of the JNK signalling pathway in self-renewing and differentiated stem-like glioblastoma cells.(a–b) Self-renewing (maintained under the monolayer stem cell culture condition; SR) and differentiated (cultured under the differentiation-inducing condition for 1 week; Diff) stem-like glioblastoma cells were subjected to immunoblot analysis to examine the activation/phosphorylation status of the JNK signalling pathway (a) and that of AKT, ERK, and p38 (b).
Mentions: To identify candidate regulators of the stem-like properties (i.e., the capacity to self-renew and to undergo multi-lineage differentiation, see Supplementary Fig. 1 for characterization of the stem-like glioblastoma cells used in this study) of stem-like glioblastoma cells, we searched for molecules differentially expressed and/or activated in self-renewing and differentiated stem-like glioblastoma cells. We found that, compared to their differentiated counterparts, self-renewing stem-like glioblastoma cells have elevated levels of JNK phosphorylation at the activating phosphorylation sites. We also found that the increased JNK phosphorylation is accompanied by increased c-Jun phosphorylation at the cognate JNK phosphorylation site, indicating increased JNK pathway activation in self-renewing cells (Fig. 1a). Notably, whereas the differential activation status of other signalling pathways implicated in glioblastoma biology and of related MAPK superfamily members1116 was inconsistent and varied depending on the cell line tested (Fig. 1b), the JNK pathway was consistently activated in self-renewing cells relative to differentiated cells in all the stem-like glioblastoma cell lines tested including those directly derived from glioblastoma patients (patient-derived stem-like glioblastoma cells) as well as those established from conventional, serum-cultured cell lines (Fig. 1a).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, 990-9585, Japan.

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.

Show MeSH
Related in: MedlinePlus