TMZ regulates GBM stemness <i>via</i> MMP14‐DLL4‐Notch3 pathway

Ulasov, Ilya V.; Mijanović, Olja; Savchuk, Solomiia; González-Buendía, Edgar; Sonabend, Adam M.; Xiao, Ting; Timashev, Petr; Lesniak, Maciej S.

doi:10.1002/ijc.32636

Cited by 18 publications

(13 citation statements)

References 57 publications

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“…Subsequently, CHAC1 binds to Notch3 protein, which reduces the generation of N3ICD, thus preventing Notch3 signaling ( Chen et al, 2017 ). However, a recent study found that TMZ can also activate DLL4/Notch3 signaling to maintain CSC properties in GBM by upregulating MMP14 expression ( Ulasov et al, 2020 ). Thus, the effect of TMZ on Notch3 signaling needs further exploration.…”

Section: Notch3-targeting Strategies For Cancer Therapymentioning

confidence: 99%

The Role of Notch3 Signaling in Cancer Stemness and Chemoresistance: Molecular Mechanisms and Targeting Strategies

Xiu

Wang

et al. 2021

Front. Mol. Biosci.

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Aberrant Notch signaling profoundly affects cancer progression. Especially the Notch3 receptor was found to be dysregulated in cancer, where its expression is correlated with worse clinicopathological features and poor prognosis. The activation of Notch3 signaling is closely related to the activation of cancer stem cells (CSCs), a small subpopulation in cancer that is responsible for cancer progression. In addition, Notch3 signaling also contributes to tumor chemoresistance against several drugs, including doxorubicin, platinum, taxane, epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitors (TKIs) and gemcitabine, through complex mechanisms. In this review, we mainly focus on discussing the molecular mechanisms by which Notch3 modulates cancer stemness and chemoresistance, as well as other cancer behaviors including metastasis and angiogenesis. What’s more, we propose potential treatment strategies to block Notch3 signaling, such as non-coding RNAs, antibodies and antibody-drug conjugates, providing a comprehensive reference for research on precise targeted cancer therapy.

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Section: Notch3-targeting Strategies For Cancer Therapymentioning

confidence: 99%

The Role of Notch3 Signaling in Cancer Stemness and Chemoresistance: Molecular Mechanisms and Targeting Strategies

Xiu

Wang

et al. 2021

Front. Mol. Biosci.

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“…A limiting dilution assay also showed that TMZ treatment up to a concentration of 200 µM did not affect TS formation, and even 500 µM of TMZ did not completely block TS formation (Figure 1B). Since stemness of glioblastoma is one of the major causes of glioblastoma resistance to TMZ [34], we tested whether resistance to TMZ was reduced by differentiation of TS cells. Serum addition for seven days caused TS cells to adhere to the culture plate and reduce stemness [30].…”

Section: Resultsmentioning

confidence: 99%

Gossypol Suppresses Growth of Temozolomide-Resistant Glioblastoma Tumor Spheres

et al. 2019

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Temozolomide is the current first-line treatment for glioblastoma patients but, because many patients are resistant to it, there is an urgent need to develop antitumor agents to treat temozolomide-resistant glioblastoma. Gossypol, a natural polyphenolic compound, has been studied as a monotherapy or combination therapy for the treatment of glioblastoma. The combination of gossypol and temozolomide has been shown to inhibit glioblastoma, but it is not clear yet whether gossypol alone can suppress temozolomide-resistant glioblastoma. We find that gossypol suppresses the growth of temozolomide-resistant glioblastoma cells in both tumor sphere and adherent culture conditions, with tumor spheres showing the greatest sensitivity. Molecular docking and binding energy calculations show that gossypol has a similar affinity to the Bcl2 (B-cell lymphoma 2) family of proteins and several dehydrogenases. Gossypol reduces mitochondrial membrane potential and cellular ATP levels before cell death, which suggests that gossypol inhibits several dehydrogenases in the cell’s metabolic pathway. Treatment with a Bcl2 inhibitor does not fully explain the effect of gossypol on glioblastoma. Overall, this study demonstrates that gossypol can suppress temozolomide-resistant glioblastoma and will be helpful for the refinement of gossypol treatments by elucidating some of the molecular mechanisms of gossypol in glioblastoma.

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“…Notch1 expression and activation contribute to glial cell transformation and glioma growth/survival, migration/invasion through Ras ( Kanamori et al, 2007 ), β-catenin, NF-κB, AKT activation and downregulation of PTEN ( Zhang et al, 2012 ; El Hindy et al, 2013 ). Recently, Ulasov et al found that Temozolomide (TMZ) facilitates nuclear translocation of MMP14, followed by extracellular release of canonical Notch1 and Notch3 ligand Dll4, which in turn promotes cleavage of Notch3 and its nuclear translocation and induces glioma sphering ability and stemness ( Ulasov et al, 2020 ). Notch4 is proposed as a less differentiated marker for glioma cells, and Notch4 expression increases from low-grade astrocytoma to high-graded GBM ( El Hindy et al, 2013 ; Dell'albani et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

TRPM7 Induces Tumorigenesis and Stemness Through Notch Activation in Glioma

et al. 2020

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We have reported that transient receptor potential melastatin-related 7 (TRPM7) regulates glioma stem cells (GSC) growth and proliferation through Notch, STAT3-ALDH1, and CD133 signaling pathways. In this study, we determined the major contributor(s) to TRPM7 mediated glioma stemness by further deciphering each individual Notch signaling. We first determined whether TRPM7 is an oncotarget in glioblastoma multiforme (GBM) using the Oncomine database. Next, we determined whether TRPM7 silencing by siRNA TRPM7 (siTRPM7) induces cell growth arrest or apoptosis to reduce glioma cell proliferation using cell cycle analysis and annexin V staining assay. We then examined the correlations between the expression of TRPM7 and Notch signaling activity as well as the expression of GSC markers CD133 and ALDH1 in GBM by downregulating TRPM7 through siTRPM7 or upregulating TRPM7 through overexpression of human TRPM7 (M7-wt). To distinguish the different function of channel and kinase domain of TRPM7, we further determined how the α-kinase-dead mutants of TRPM7 (α-kinase domain deleted/M7-DK and K1648R point mutation/M7-KR) affect Notch activities and CD133 and ALDH1 expression. Lastly, we determined the changes in TRPM7-mediated regulation of glioma cell growth/proliferation, cell cycle, and apoptosis by targeting Notch1. The Oncomine data revealed a significant increase in TRPM7 mRNA expression in anaplastic astrocytoma, diffuse astrocytoma, and GBM patients compared to that in normal brain tissues. TRPM7 silencing reduced glioma cell growth by inhibiting cell entry into S and G2/M phases and promoting cell apoptosis. TRPM7 expression in GBM cells was found to be positively correlated with Notch1 signaling activity and CD133 and ALDH1 expression; briefly, downregulation of TRPM7 by siTRPM7 decreased Notch1 signaling whereas upregulation of TRPM7 increased Notch1 signaling. Interestingly, kinase-inactive mutants (M7-DK and M7-KR) resulted in reduced activation of Notch1 signaling and decreased expression of CD133 and ALDH1 compared to that of wtTRPM7. Finally, targeting Notch1 effectively suppressed TRPM7-induced growth and proliferation of glioma cells through cell G1/S arrest and apoptotic induction. TRPM7 is responsible for sustained Notch1 signaling activation, enhanced expression of GSC markers CD133 and ALDH1, and regulation of glioma stemness, which contributes to malignant glioma cell growth and invasion.

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TMZ regulates GBM stemness via MMP14‐DLL4‐Notch3 pathway

Cited by 18 publications

References 57 publications

The Role of Notch3 Signaling in Cancer Stemness and Chemoresistance: Molecular Mechanisms and Targeting Strategies

The Role of Notch3 Signaling in Cancer Stemness and Chemoresistance: Molecular Mechanisms and Targeting Strategies

Gossypol Suppresses Growth of Temozolomide-Resistant Glioblastoma Tumor Spheres

TRPM7 Induces Tumorigenesis and Stemness Through Notch Activation in Glioma

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