Momelotinib sensitizes glioblastoma cells to temozolomide by enhancement of autophagy via JAK2/STAT3 inhibition

Li, Shipeng; Li, Anqi; Xu, Yulun; Yu, Xuezhong

doi:10.3892/or.2019.6970

Cited by 25 publications

(23 citation statements)

References 41 publications

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“…These tumor inhibitory and tumor microenvironment normalizing effects of pacritinib could be attributed to the suppression of STAT3/JAK2 signaling. Our observations were supported by a recent report that the inhibition of the JAK/STAT3 pathway resulted in disrupted intercellular communications between microglia and GBM cells [35] and pronounced anti-GBM effects [36,37]. In addition, we found that pacritinib treatment was able to suppress the number of miR-21-enriched exosomes secreted by GAMs.…”

Section: Discussionsupporting

confidence: 89%

Preclinical Evidence of STAT3 Inhibitor Pacritinib Overcoming Temozolomide Resistance via Downregulating miR-21-Enriched Exosomes from M2 Glioblastoma-Associated Macrophages

Chuang

Liu

et al. 2019

JCM

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Background: The tumor microenvironment (TME) plays a crucial role in virtually every aspect of tumorigenesis of glioblastoma multiforme (GBM). A dysfunctional TME promotes drug resistance, disease recurrence, and distant metastasis. Recent evidence indicates that exosomes released by stromal cells within the TME may promote oncogenic phenotypes via transferring signaling molecules such as cytokines, proteins, and microRNAs. Results: In this study, clinical GBM samples were collected and analyzed. We found that GBM-associated macrophages (GAMs) secreted exosomes which were enriched with oncomiR-21. Coculture of GAMs (and GAM-derived exosomes) and GBM cell lines increased GBM cells’ resistance against temozolomide (TMZ) by upregulating the prosurvival gene programmed cell death protein 4 (PDCD4) and stemness markers SRY (sex determining region y)-box 2 (Sox2), signal transducer and activator of transcription 3 (STAT3), Nestin, and miR-21-5p and increasing the M2 cytokines interleukin 6 (IL-6) and transforming growth factor beta 1(TGF-β1) secreted by GBM cells, promoting the M2 polarization of GAMs. Subsequently, pacritinib treatment suppressed GBM tumorigenesis and stemness; more importantly, pacritinib-treated GBM cells showed a markedly reduced ability to secret M2 cytokines and reduced miR-21-enriched exosomes secreted by GAMs. Pacritinib-mediated effects were accompanied by a reduction of oncomiR miR-21-5p, by which the tumor suppressor PDCD4 was targeted. We subsequently established patient-derived xenograft (PDX) models where mice bore patient GBM and GAMs. Treatment with pacritinib and the combination of pacritinib and TMZ appeared to significantly reduce the tumorigenesis of GBM/GAM PDX mice as well as overcome TMZ resistance and M2 polarization of GAMs. Conclusion: In summation, we showed the potential of pacritinib alone or in combination with TMZ to suppress GBM tumorigenesis via modulating STAT3/miR-21/PDCD4 signaling. Further investigations are warranted for adopting pacritinib for the treatment of TMZ-resistant GBM in clinical settings.

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Section: Discussionsupporting

confidence: 89%

Preclinical Evidence of STAT3 Inhibitor Pacritinib Overcoming Temozolomide Resistance via Downregulating miR-21-Enriched Exosomes from M2 Glioblastoma-Associated Macrophages

Chuang

Liu

et al. 2019

JCM

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show abstract

“…This tumor inhibitory and tumor microenvironment normalizing effects of pacritinib could be attributed to the suppression of STAT3/JAK2 signaling. Our observations were supported by a recent report that the inhibition of JAK/STAT3 pathway resulted in the disrupted intercellular communications between microglia and GBM cells [35] and pronounced anti-GBM effects [36,37]. In addition, we found that pacritinib treatment was able to suppress the number of miR-21-enriched exosomes secreted by GAMs.…”

Section: Discussionsupporting

confidence: 90%

Preclinical Evidence of STAT3 Inhibitor, Pacritinib, Overcomes Temozolomide Resistance via Down-Regulating miR-21-enriched Exosomes from M2 Glioblastoma-Associated Macrophages

Chuang¹,

Su²,

Liu³

et al. 2019

Preprint

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Background: Tumor microenvironment (TME) plays a crucial role in virtually every aspect of tumorigenesis of glioblastoma multiforme (GBM). The dysfunctional TME promotes drug resistance, disease recurrence and distant metastasis. Recent evidence indicates that exosomes released by stromal cells within TME may promote oncogenic phenotypes via transferring signaling molecules such as cytokines, proteins and microRNAs. Results: In this study, clinical GBM samples were collected and analyzed. We found that GBM-associated macrophages (GAMs) secreted exosomes which were enriched with oncomiR-21. Co-culture of GAMs (and GAM derived exosomes) and GBM cell lines resulted in the increased GBM cells’ resistance against temozolomide (TMZ) by upregulating pro-survival gene, PDCD4 and stemness markers Sox2, STAT3, Nestin and miR-21-5p and increased M2 cytokines, IL-6 and TGF-β1 secreted by GBM cells, promoting the M2 polarization of GAMs. Subsequently, pacritinib treatment suppressed GBM tumorigenesis and stemness; more importantly, pacritinib-treated GBM cells showed markedly reduced ability to secret M2 cytokines and reduced miR-21 enriched exosomes secreted by GAMs. Pacritinib-mediated effects were accompanied by a reduction of oncomiR miR-21-5p, by which tumor suppressor PDCD4 was targeted. We subsequently established a patient-derived xenograft models where mice bore patient GBM and GAMs. The treatment of pacritinib, and the combination of pacritinib/TMZ appeared to significantly reduce tumorigenesis of GBM/GAM PDX mice, overcome TMZ-resistance, and M2 polarization of GAMs. Conclusion: In summation, we showed that potential of pacritinib alone or in combination with TMZ for suppressing GBM tumorigenesis via modulating STAT3/miR-21/PDCD4 signaling. Further investigations are warranted for adopting pacritinib for the treatment of TMZ-resistant GBM in the clinical settings.

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“…Regulating autophagy was the key process involved in the chemoresistance and radioresistance of GBM . Sensitizing GBM cells to temozolomide via regulating autophagy has been widely reported by scholars . With respect to the interplay between autophagy and AS, splicing autophagy‐related genes has been reported to influence autophagy .…”

Section: Discussionmentioning

confidence: 99%

Role of alternative splicing signatures in the prognosis of glioblastoma

Xie

Dang

et al. 2019

Cancer Medicine

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Background Increasing evidence has validated the crucial role of alternative splicing (AS) in tumors. However, comprehensive investigations on the entirety of AS and their clinical value in glioblastoma (GBM) are lacking. Methods The AS profiles and clinical survival data related to GBM were obtained from The Cancer Genome Atlas database. Univariate and multivariate Cox regression analyses were performed to identify survival‐associated AS events. A risk score was calculated, and prognostic signatures were constructed using seven different types of independent prognostic AS events, respectively. The Kaplan‐Meier estimator was used to display the survival of GBM patients. The receiver operating characteristic curve was applied to compare the predictive efficacy of each prognostic signature. Enrichment analysis and protein interactive networks were conducted using the gene symbols of the AS events to investigate important processes in GBM. A splicing network between splicing factors and AS events was constructed to display the potential regulatory mechanism in GBM. Results A total of 2355 survival‐associated AS events were identified. The splicing prognostic model revealed that patients in the high‐risk group have worse survival rates than those in the low‐risk group. The predictive efficacy of each prognostic model showed satisfactory performance; among these, the Alternate Terminator (AT) model showed the best performance at an area under the curve (AUC) of 0.906. Enrichment analysis uncovered that autophagy was the most enriched process of prognostic AS gene symbols in GBM. The protein network revealed that UBC, VHL, KCTD7, FBXL19, RNF7, and UBE2N were the core genes in GBM. The splicing network showed complex regulatory correlations, among which ELAVL2 and SYNE1_AT_78181 were the most correlated (r = −.506). Conclusions Applying the prognostic signatures constructed by independent AS events shows promise for predicting the survival of GBM patients. A splicing regulatory network might be the potential splicing mechanism in GBM.

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Momelotinib sensitizes glioblastoma cells to temozolomide by enhancement of autophagy via JAK2/STAT3 inhibition

Cited by 25 publications

References 41 publications

Preclinical Evidence of STAT3 Inhibitor Pacritinib Overcoming Temozolomide Resistance via Downregulating miR-21-Enriched Exosomes from M2 Glioblastoma-Associated Macrophages

Preclinical Evidence of STAT3 Inhibitor Pacritinib Overcoming Temozolomide Resistance via Downregulating miR-21-Enriched Exosomes from M2 Glioblastoma-Associated Macrophages

Preclinical Evidence of STAT3 Inhibitor, Pacritinib, Overcomes Temozolomide Resistance via Down-Regulating miR-21-enriched Exosomes from M2 Glioblastoma-Associated Macrophages

Role of alternative splicing signatures in the prognosis of glioblastoma

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