Wnt/β-catenin signaling pathway induces autophagy-mediated temozolomide-resistance in human glioblastoma

Yun, Eun Joo; Kim, Sangwoo; Hsieh, Jer Tsong; Baek, Seung Tae

doi:10.1038/s41419-020-02988-8

Cited by 69 publications

(69 citation statements)

References 55 publications

(82 reference statements)

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“…Consistent with these findings, activation of the canonical Wnt/β-catenin signaling cascade induces MGMT expression, and its inhibition augments the cytotoxic effects of TMZ [44]. Recently, it was shown that Wnt pathway may contribute to TMZ resistance through induction of autophagy [45] and that Wnt activation upon TMZ treatment is mediated by PI3K/Akt pathway [46].…”

Section: Discussionmentioning

confidence: 66%

Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries

Rocha

Silva

et al. 2020

Cells

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Glioblastoma is a severe type of brain tumor with a poor prognosis and few therapy options. Temozolomide (TMZ) is one of these options, however, with limited success, and failure is mainly due to tumor resistance. In this work, genome-wide CRISPR-Cas9 lentiviral screen libraries for gene knockout or activation were transduced in the human glioblastoma cell line, aiming to identify genes that modulate TMZ resistance. The sgRNAs enriched in both libraries in surviving cells after TMZ treatment were identified by next-generation sequencing (NGS). Pathway analyses of gene candidates on knockout screening revealed several enriched pathways, including the mismatch repair and the Sonic Hedgehog pathways. Silencing three genes ranked on the top 10 list (MSH2, PTCH2, and CLCA2) confirm cell protection from TMZ-induced death. In addition, a CRISPR activation library revealed that NRF2 and Wnt pathways are involved in TMZ resistance. Consistently, overexpression of FZD6, CTNNB1, or NRF2 genes significantly increased cell survival upon TMZ treatment. Moreover, NRF2 and related genes detected in this screen presented a robust negative correlation with glioblastoma patient survival rates. Finally, several gene candidates from knockout or activation screening are targetable by inhibitors or small molecules, and some of them have already been used in the clinic.

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Section: Discussionmentioning

confidence: 66%

Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries

Rocha

Silva

et al. 2020

Cells

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“…Meanwhile, based on the IC 50 value of si-CRNDE group in three cell lines (98.3 μM, 102.3 μM and 78.9 μM, respectively, Fig. 2 a) and referred to similar studies [ 28 , 29 ], we chose the TMZ concentration of 100 μM for subsequent experiments. Then, the effect of CRNDE expression on cell proliferation was assessed by clone formation assays in three cell lines treated with or without the treatment of TMZ at 100 μM for 72 h. The results revealed that the number of colonies was reduced in silence CRNDE group compared with control group without TMZ treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

Knockdown lncRNA CRNDE enhances temozolomide chemosensitivity by regulating autophagy in glioblastoma

et al. 2021

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Background The regulatory roles of long non-coding RNA (lncRNA) CRNDE in temozolomide (TMZ) chemoresistance to glioblastoma multiforme (GBM) are still poorly understood. Therefore, the function, characteristics, and possible mechanism of CRNDE in TMZ-induced chemoresistance to GBM were explored. Methods Firstly, the expression level of CRNDE in 58 cases of glioma tissue specimens and 30 cases of normal brain tissues were tested by qRT-PCR. Meanwhile, the correlation between CRNDE expression level, the clinicopathological characteristics, and survival time of patients with glioma were analyzed. Then, the CRNDE expression in various glioma cell lines was detected, and CRNDE knockdown cell models were constructed. Subsequently, to explore the effect of CRNDE on chemosensitivity to TMZ, cell viability was detected by the CCK-8 assay and IC50 values, and cell proliferation was detected by cell clone assay and EdU assay, as well as cell survival was detected by apoptosis with flow cytometry under TMZ treatment. Further, the expression of drug-resistance protein ABCG2, autophagy related proteins, and PI3K/Akt/mTOR pathway were measured by western blot or qRT-PCR in TMZ-treated glioma cells. Finally, the mouse tumor xenograft model was established and the tumor volume and weight were measured, and ABCG2 expression was conducted by immunohistochemistry assay. Results The integrated results demonstrated lncRNA CRNDE was a poor prognosis factor for GBM patient, which was upregulated in patients who were resistant to TMZ, and closely associated with chemotherapeutic response status to TMZ treatment. Further, functional assays revealed that knockdown of CRNDE could notably reduce glioma cell viability and proliferation, and elevate cell apoptosis to enhance the chemosensitivity to TMZ in vitro and in vivo. Mechanistically, the depression of CRNDE could diminish the expression of LC3 II/I, Beclin1 and Atg5 and increase the p62 expression level to inhibit autophagy due to the activation of PI3K/Akt/mTOR pathway as well as highly correlated with ABCG2 expression. Conclusions Overall, the study provided that lncRNA CRNDE is a reliable clinical predictor of outcome and prognosis and a potential biomarker for predicting TMZ treatment response in GBM by modulating the autophagy through PI3K/Akt/mTOR pathway and ABCG2 expression which may be a novel therapeutic target for regulating TMZ sensitivity to GBM.

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“…It was found that TMZ-induced protective autophagy reduces ALDH expression, thereby contributing to the chemoresistance in glioma cells [146]. Similarly, Yun et al recently explained the role of the DOC-2/DAB2 interacting protein (DAB2IP), which is a member of the Ras-GTPase activating proteins in chemoresistance in glioblastoma cell lines [147]. DAB2IP enhanced the sensitivity of A172 and U373 cells to TMZ via suppressing the protective autophagy through downregulating ATG9B expression.…”

Section: Targeting Autophagy To Overcome Chemoresistance In Glioblastoma Cellsmentioning

confidence: 96%

Deciphering the Role of Autophagy in Treatment of Resistance Mechanisms in Glioblastoma

Khan

Baig

Mahfooz

et al. 2021

IJMS

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Autophagy is a process essential for cellular energy consumption, survival, and defense mechanisms. The role of autophagy in several types of human cancers has been explicitly explained; however, the underlying molecular mechanism of autophagy in glioblastoma remains ambiguous. Autophagy is thought to be a “double-edged sword”, and its effect on tumorigenesis varies with cell type. On the other hand, autophagy may play a significant role in the resistance mechanisms against various therapies. Therefore, it is of the utmost importance to gain insight into the molecular mechanisms deriving the autophagy-mediated therapeutic resistance and designing improved treatment strategies for glioblastoma. In this review, we discuss autophagy mechanisms, specifically its pro-survival and growth-suppressing mechanisms in glioblastomas. In addition, we try to shed some light on the autophagy-mediated activation of the cellular mechanisms supporting radioresistance and chemoresistance in glioblastoma. This review also highlights autophagy’s involvement in glioma stem cell behavior, underlining its role as a potential molecular target for therapeutic interventions.

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Wnt/β-catenin signaling pathway induces autophagy-mediated temozolomide-resistance in human glioblastoma

Cited by 69 publications

References 55 publications

Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries

Revealing Temozolomide Resistance Mechanisms via Genome-Wide CRISPR Libraries

Knockdown lncRNA CRNDE enhances temozolomide chemosensitivity by regulating autophagy in glioblastoma

Deciphering the Role of Autophagy in Treatment of Resistance Mechanisms in Glioblastoma

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