Ivacaftor Inhibits Glioblastoma Stem Cell Maintenance and Tumor Progression

Liu, Kun; Pu, Jun; Nie, Zhi; Shi, Yuchen; Jiang, Liping; Wu, Qisheng; Chen, Yongbin; Yang, Cuiping

doi:10.3389/fcell.2021.678209

Cited by 13 publications

(11 citation statements)

References 33 publications

(39 reference statements)

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“…Recently, several innovative pre-clinical studies have emerged to enhance tumor inhibiting efficacy of TMZ [ 4 , 7 , 33 ]. Different treatment strategies based on various mechanisms of TMZ resistance can reduce GBM resistance to TMZ to some extent both in vitro and in vivo, and may offer new hope to improve GBM patients prognosis [ 8 , 11 , 12 , 34 ]. More studies have well demonstrated that GSCs were more resistant to TMZ than their differentiated progeny cells [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

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METTL3 knockdown promotes temozolomide sensitivity of glioma stem cells via decreasing MGMT and APNG mRNA stability

et al. 2023

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Chemo-resistance hinders the therapeutic efficacy of temozolomide (TMZ) in treating glioblastoma multiforme (GBM). Recurrence of GBM even after combination of maximal tumor resection, concurrent radio-chemotherapy, and systemic TMZ applocation is inevitable and attributed to the high therapeutic resistance of glioma stem cells (GSCs), which can survive, evolve, and initiate tumor tissue remodeling, the underlying mechanisms of GSCs chemo-resistance, have not been fully elucidated up-to-now. Emerging evidence showed that METTL3-mediated N6-methyladenosine (m6A) modification contributed to the self-renew and radio-resistance in GSCs, however, its role on maintenance of TMZ resistance of GSCs has not been clarified and need further investigations. We found that the cell viability and half-maximal inhibitory concentration (IC50) of GSCs against TMZ significantly decreased after GSCs underwent serum-induced differentiation to adherent growth of tumor cells. Besides, METTL3 expression and total m6A modification declined dramatically in consistence with GSCs differentiation. Knockdown of METTL3 weakened self-renew, proliferation and TMZ IC50 of GSCs, whereas enhanced TMZ induced γH2AX level, indicating upregulation of double-strand DNA damage. We also found that mRNA stability of two critical DNA repair genes (MGMT and APNG) was regulated by METTL3-mediated m6A modification. In conclusion, we speculated that METTL3-mediated m6A modification of MGMT and APNG mRNAs played crucial roles on suppression of TMZ sensitivity of GSCs, which suggest a potential new therapeutic target of METTL3 against GBM.

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Section: Discussionmentioning

confidence: 99%

“…[2,[4][5][6][7][8]. Several studies have suggested that GBMderived glioma stem cells (GSCs) may play vital roles on formation of GBM resistance to TMZ [9][10][11]. GSCs had the features of selfrenewal, infinite proliferation, multi-potential differentiation, strong infiltration, and migration abilities [11,12].…”

Section: Introductionmentioning

confidence: 99%

METTL3 knockdown promotes temozolomide sensitivity of glioma stem cells via decreasing MGMT and APNG mRNA stability

et al. 2023

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“…Many inhibitors have been reported to induce cancer regression in a different type of cancer, yet only a small portion of them have been applied in clinical trials ( 149 – 151 ). Recently, the characterization and application of antisense oligonucleotide (ASO) opens a new avenue for the development of cancer therapeutics, and many of them have been implemented in different clinical trials ( 152 – 154 ).…”

Section: Clinical Relevance Of Lncrna In Tcmentioning

confidence: 99%

The Emerging Landscapes of Long Noncoding RNA in Thyroid Carcinoma: Biological Functions and Clinical Significance

et al. 2021

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Thyroid carcinoma (TC) is one of the most prevalent primary endocrine tumors, and its incidence is steadily and gradually increasing worldwide. Accumulating evidence has revealed the critical functions of long noncoding RNAs (lncRNAs) in the tumorigenesis and development of TC. Many TC-associated lncRNAs have been documented to be implicated in TC malignant behaviors, including abnormal cell proliferation, enhanced stem cell properties and aggressiveness, and resistance to therapeutics, through interaction with proteins, DNA, or RNA or encoding small peptides. Therefore, further elucidating the lncRNA dysregulation sheds additional insights into TC tumorigenesis and progression and opens new avenues for the early diagnosis and clinical therapy of TC. In this review, we summarize the abnormal expression of lncRNA in TC and the fundamental characteristics in TC tumorigenesis and development. Additionally, we introduce the potential prognostic and therapeutic significance of lncRNAs in TC.

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“…Glioblastoma (GBM) is a primary brain tumor of the central nervous system in adults. It has been well-recognized that GBM was initiated by a subpopulation of cells termed glioblastoma stem cells (GSCs) 1 , 2 . Central nervous system (CNS) gliomas are classified into 4 grades according to the WHO classification.…”

Section: Introductionmentioning

confidence: 99%

“…The median survival of patients with GBM is only 14.6 months. Currently, conventional treatment includes neurosurgery, temozolomide (TMZ) dependent chemotherapy 1 , 2 , and chemotherapy. Although GBM cells rarely metastasize to other body organs, the treatment of GBM remains ineffective.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of STAT3 signaling as critical molecular event in HUC-MSCs suppressed Glioblastoma Cells

Wang¹,

Zhang²,

Liu³

et al. 2023

J. Cancer

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Objective: We investigated the effect of human umbilical cord mesenchymal stem cells (HUC-MSCs) supernatants on proliferation, migration, invasion, and apoptosis in glioblastoma (GBM) cell lines RG-2, U251, U87-MG, and LN-428, as well as their apoptosis and autophagy-mediated through IL-6/JAK2/STAT3 signaling pathway to explore the molecular mechanisms. Methods: In this study, RG-2, U251, U87-MG, and LN-428 cells were treated with 9 mg/ml HUC-MSCs supernatants. Their responses to HUC-MSCs supernatants treatment and the status of STAT3 signaling were analyzed by multiple experimental approaches to elucidate the importance of HUC-MSCs supernatants for GBM. Results: The results demonstrated that after treatment with HUC-MSCs supernatants, in vitro proliferation of RG-2, U251, U87-MG, and LN-428 cells were inhibited, and their sustained growth was also blocked. RG-2, U251, and U87-MG cells showed significant S phase accumulation, while LN-428 cells were blocked in G0/G1 phase. Their migratory invasive capacities were inhibited, and their apoptosis and autophagy ratios were increased. These effects were mediated through the IL-6/JAK2/STAT3 and its downstream signaling pathway. Conclusion: Our data showed that HUC-MSCs supernatants had anti-tumor effects on GBM cells. It inhibited the proliferation, migration, and invasion of GBM cells and promoted their apoptosis. Negative regulation of the IL-6/JAK2/STAT3 signaling pathway enhanced apoptosis and autophagy in tumor cells, thereby improving the therapeutic effect on GBM.

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Ivacaftor Inhibits Glioblastoma Stem Cell Maintenance and Tumor Progression

Cited by 13 publications

References 33 publications

METTL3 knockdown promotes temozolomide sensitivity of glioma stem cells via decreasing MGMT and APNG mRNA stability

METTL3 knockdown promotes temozolomide sensitivity of glioma stem cells via decreasing MGMT and APNG mRNA stability

The Emerging Landscapes of Long Noncoding RNA in Thyroid Carcinoma: Biological Functions and Clinical Significance

Inhibition of STAT3 signaling as critical molecular event in HUC-MSCs suppressed Glioblastoma Cells

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