Overcoming therapeutic resistance in glioblastoma: the way forward

Osuka, Satoru; Meir, Erwin G. Van

doi:10.1172/jci89587

Cited by 379 publications

(308 citation statements)

References 175 publications

(225 reference statements)

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“…Glioblastoma is a lethal type of malignant primary brain tumour in adults. Complete resection is currently difficult, although therapeutic approaches such as surgical treatment and chemotherapy are improving . It has been previously reported that Bip/Grp78 is a novel candidate target for improving chemosensitivity against malignant glioma, and Bip suppression in glioblastoma cells would be a novel approach to improve treatment .…”

Section: Resultsmentioning

confidence: 99%

“…Complete resection is currently difficult, although therapeutic approaches such as surgical treatment and chemotherapy are improving. [23] It has been previously reported that Bip/Grp78 is a novel candidate target for improving chemosensitivity against malignant glioma, and Bip suppression in glioblastoma cells would be a novel approach to improve treatment. [24] We first evaluated the effects of several chemical chaperones on Bip promoter activity in glioblastoma cells by bioluminescence imaging at the single cell level.…”

Section: Evaluation Of Chemical Chaperones Using Real Time Monitorimentioning

confidence: 99%

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Evaluation of chemical chaperones based on the monitoring of Bip promoter activity and visualization of extracellular vesicles by real‐time bioluminescence imaging

et al. 2017

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It is known that endoplasmic reticulum (ER) stress in cells and extracellular vesicles (EVs) plays a significant role in cancer cells, therefore the evaluation of compounds that can regulate ER stress and EV secretion would be a suitable system for further screening and development of new drugs. In this study, we evaluated chemical chaperones derived from natural products based on monitoring Bip/GRP78 promoter activity during cancer cell growth, at the level of the single cell, by a bioluminescence microscopy system that had several advantages compared with fluorescence imaging. It was found that several chemical chaperones, such as ferulic acid (FA), silybin, and rutin, affected the activity. We visualized EVs from cancer cells using bioluminescence imaging and showed that several EVs could be observed when using CD63 fused with NanoLuc luciferase, which has a much smaller molecular weight and higher intensity than conventional firefly luciferase. We then examined the effects of the chemical chaperones on EVs from cancer cells by bioluminescence imaging and quantified the expression of CD63 in these EVs. It was found that the chemical chaperones examined in this study affected CD63 levels in EVs. These results showed that imaging at the level of the single cell using bioluminescence is a powerful tool and could be used to evaluate chemical chaperones and EVs from cancer cells. This approach may produce new information in this field when taken together with conventional and classical methods.

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Section: Resultsmentioning

confidence: 99%

Section: Evaluation Of Chemical Chaperones Using Real Time Monitorimentioning

confidence: 99%

Evaluation of chemical chaperones based on the monitoring of Bip promoter activity and visualization of extracellular vesicles by real‐time bioluminescence imaging

et al. 2017

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“…Glioma accounts for 46% of all primary intracranial tumors in the central nervous system . Increasing evidence has suggested that rapid acquired therapeutic resistance is the major cause of the failure of standard comprehensive treatments, leading to the recurrence and high mortality of glioma . Various molecular pathways have been shown to be responsible for the acquisition of therapeutic resistance in glioma .…”

Section: Discussionmentioning

confidence: 99%

Combined elevation of TRIB2 and MAP3K1 indicates poor prognosis and chemoresistance to temozolomide in glioblastoma

et al. 2019

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Introduction Glioblastoma (GBM) is the most lethal primary malignant brain tumor in adults with poor survival due to acquired therapeutic resistance and rapid recurrence. Currently, the standard clinical strategy for glioma includes maximum surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy; however, the median survival of patients with GBM remains poor despite these comprehensive therapies. Therefore, the identification of new prognostic biomarkers is urgently needed to evaluate the malignancy and long‐term outcome of glioma. Aims To further investigate prognostic biomarkers and potential therapeutic targets for GBM. Results In this study, we identified tribbles pseudokinase 2 (TRIB2) as one of the genes that is most correlated with pathological classification, radioresistance, and TMZ resistance in glioma. Additionally, the expression of mitogen‐activated protein kinase kinase kinase 1 (MAP3K1) showed a strong correlation with TRIB2. Moreover, a combined increase in TRIB2 and MAP3K1 was observed in GBM and indicated a poor prognosis of patients with glioma. Finally, enriched TRIB2 expression and MAP3K1 expression were shown to be associated with resistance to TMZ and radiotherapy. Conclusion Combined elevation of TRIB2 and MAP3K1 could be novel prognostic biomarkers and potential therapeutic targets to evaluate the malignancy and long‐term outcomes of GBM.

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“…Despite the development of treatment options, including surgery, chemotherapy and radiotherapy, the median survival time of patients with these tumors is approximately 1 year after diagnosis. The major limitations of glioma treatment are the prevalence of recurrence after surgery, resulting from infiltration into surrounding tissues and intrinsic or acquired resistance to chemo‐ and radiotherapy . Therefore, new therapeutic targets and tools for the treatment of glioblastomas (GBMs) should be explored further.…”

Section: Introductionmentioning

confidence: 99%

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

Wang

Xia

et al. 2019

Intl Journal of Cancer

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JNK activity has been implicated in the malignant proliferation, invasion and drug‐resistance of glioma cells (GCs), but the molecular mechanisms underlying JNK activation are currently unknown. Here, we reported that MKK7, not MKK4, directly activates JNK in GCs and exerts oncogenic effects on tumor formation. Notably, MKK7 expression in glioma tissues was closely correlated with the grade of the glioma and JNK/c‐Jun activation. Mechanistically, MKK7 transcription critically depends on the complexes formed by HDAC4 and the transcriptional factors SP1 and Krüppel‐like factor‐5 (KLF5), wherein HDAC4 directly deacetylates both SP1 and KLF5 and synergistically upregulates MKK7 transcription through two SP1 sites located on its promoter. In contrast, the increases in acetylated‐SP1 and acetylated‐KLF5 after HDAC4 inhibition switched to transcriptionally suppress MKK7. Selective inhibition of HDAC4 by LMK235, siRNAs or blockage of SP1 and KLF5 by the ectopic dominant‐negative SP1 greatly reduced the malignant capacity of GCs. Furthermore, suppression of both MKK7 expression and JNK/c‐Jun activities was involved in the tumor‐growth inhibitory effects induced by LMK235 in U87‐xenograft mice. Interestingly, HDAC4 is highly expressed in glioma tissues, and the rate of HDAC4 nuclear import is closely correlated with glioma grade, as well as with MKK7 expression. Collectively, these findings demonstrated that highly expressed MKK7 contributes to JNK/c‐Jun signaling‐mediated glioma formation. MKK7 transcription, regulated by SP1 and KLF5, critically depends on HDAC4 activity, and inhibition of HDAC4 presents a potential strategy for suppressing the oncogenic roles of MKK7/JNK/c‐Jun signaling in GCs.

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Overcoming therapeutic resistance in glioblastoma: the way forward

Cited by 379 publications

References 175 publications

Evaluation of chemical chaperones based on the monitoring of Bip promoter activity and visualization of extracellular vesicles by real‐time bioluminescence imaging

Evaluation of chemical chaperones based on the monitoring of Bip promoter activity and visualization of extracellular vesicles by real‐time bioluminescence imaging

Combined elevation of TRIB2 and MAP3K1 indicates poor prognosis and chemoresistance to temozolomide in glioblastoma

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

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