Aberrant Expression of ADARB1 Facilitates Temozolomide Chemoresistance and Immune Infiltration in Glioblastoma

Lü, Can; Chen, Xi; Yan, Yuanliang; Ren, Xinxin; Wang, Xiang; Peng, Bi; Cai, Yuan; Liang, Qiuju; Xu, Zhijie; Peng, Jinwu

doi:10.3389/fphar.2022.768743

Cited by 3 publications

(3 citation statements)

References 57 publications

(54 reference statements)

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“…It reported that RNA modification regulator adenosine deaminases acting on RNA (ADARs) promote TMZ resistance by upregulating p-Akt. U343 expressing low ADARB1 may restore TMZ sensitivity in GB cells by decreased p-Akt [ 45 ]. To study whether the status of PTEN and/or Akt signaling affects the sensitivity of TMZ, we first analyzed the publicly available dataset in the Genomics of Drug Sensitivity in Cancer (GDSC) and The Cancer Genome Atlas Program (TCGA-GB) where GB samples were classified into two groups according to status of PTEN: wild type ( n = 16 in GDSC-GB and n = 102 in TCGA-GB) and mutant ( n = 17 in GDSC-GB and n = 47 in TCGA-GB).…”

Section: Resultsmentioning

confidence: 99%

Smurf1 Suppression Enhances Temozolomide Chemosensitivity in Glioblastoma by Facilitating PTEN Nuclear Translocation

Dong

Liu

et al. 2022

Cells

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The tumor suppressor PTEN mainly inhibits the PI3K/Akt pathway in the cytoplasm and maintains DNA stability in the nucleus. The status of PTEN remains therapeutic effectiveness for chemoresistance of the DNA alkylating agent temozolomide (TMZ) in glioblastoma (GB). However, the underlying mechanisms of PTEN’s interconnected role in the cytoplasm and nucleus in TMZ resistance are still unclear. In this study, we report that TMZ−induced PTEN nuclear import depends on PTEN ubiquitylation modification by Smurf1. The Smurf1 suppression decreases the TMZ−induced PTEN nuclear translocation and enhances the DNA damage. In addition, Smurf1 degrades cytoplasmic PTEN K289E (the nuclear−import−deficient PTEN mutant) to activate the PI3K/Akt pathway under TMZ treatment. Altogether, Smurf1 interconnectedly promotes PTEN nuclear function (DNA repair) and cytoplasmic function (activation of PI3K/Akt pathway) to resist TMZ. These results provide a proof−of−concept demonstration for a potential strategy to overcome the TMZ resistance in PTEN wild−type GB patients by targeting Smurf1.

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Section: Resultsmentioning

confidence: 99%

Smurf1 Suppression Enhances Temozolomide Chemosensitivity in Glioblastoma by Facilitating PTEN Nuclear Translocation

Dong

Liu

et al. 2022

Cells

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“…According to previous studies, two TMZ-resistant GBM cell lines (T98G-R and U118-R) were established and cultured ( Yan et al, 2019 ; Lu et al, 2022 ). Small interfering RNAs (siRNAs) targeting FANCD2 were purchased from Genepharma (Suzhou, China).…”

Section: Methodsmentioning

confidence: 99%

Abnormally Expressed Ferroptosis-Associated FANCD2 in Mediating the Temozolomide Resistance and Immune Response in Glioblastoma

Song

et al. 2022

Front. Pharmacol.

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Ferroptosis-related genes (FRGs) have been identified as potential targets involved in oncogenesis and cancer therapeutic response. Nevertheless, the specific roles and underlying mechanisms of FRGs in GBM and temozolomide (TMZ) resistance remain unclear. Through comprehensive bioinformatics, we found that ferroptosis-related Fanconi anemia complementation group D2 (FANCD2) was significantly up-regulated in GBM tissues, and the high expression level of FANCD2 was related to the poor prognosis in primary and recurrent GBM patients. Furthermore, FANCD2 could promote TMZ resistance by attenuating ferroptosis in GBM cells. Knockdown of FANCD2 could increase reactive oxygen species (ROS) levels and inhibit cell survival. The two characteristics were associated with ferroptosis in TMZ-resistant GBM cells T98G-R and U118-R. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that aberrantly expressed FANCD2 was potentially linked with several cancer-associated signaling pathways, including chromosome segregation, DNA replication, and cell cycle transition. In addition, we demonstrated that FANCD2 expression was positively correlated with several tumor-infiltrating lymphocytes (TILs) and multiple immune-associated signatures in GBM. Therefore, up-regulated FANCD2 could protect GBM cells from ferroptosis and promote TMZ resistance. FANCD2 may be a novel therapeutic target in GBM.

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“…The sequences of the forward and reverse primers are provided in Supplementary Table S1 . The relative expression levels were examined using the 2-ΔΔCT method, as shown in previous reports ( Lu et al, 2022 ), and all the detection-related processes were performed at least three times.…”

Section: Methodsmentioning

confidence: 99%

Upregulation of nuclear division cycle 80 contributes to therapeutic resistance via the promotion of autophagy-related protein-7-dependent autophagy in lung cancer

Chen

Zeng

et al. 2022

Front. Pharmacol.

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Lung cancer remains the leading cause of malignant mortality worldwide. Hence, the discovery of novel targets that can improve therapeutic effects in lung cancer patients is an urgent need. In this study, we screened differentially expressed genes using isobaric tags for relative and absolute quantitation (iTRAQ) analysis and datasets from the cancer genome atlas database, and found that nuclear division cycle 80 (NDC80) might act as a novel prognostic indicator of lung cancer. The expression of NDC80 was significantly increased in lung cancer tissues, as compared to normal tissues, and high expression levels of NDC80 were correlated with unfavorable survival rates. Furthermore, an in vitro analysis showed that the stable knockdown of NDC80 decreased the cell viability and increased therapeutic sensitivity in two lung cancer cell lines, A549-IRR and H1246-IRR. Moreover, gene set enrichment analysis results showed that NDC80 was enriched in autophagy-related pathways. The downregulation of NDC80 inhibited the formation of autophagosomes, and reduced the expression of autophagy-related proteins such as LC3II, Beclin-1, and p62 in lung cancer cells. To further clarify the role of NDC80 as a downstream regulator of autophagy, we validated autophagic mediators through iTRAQ analysis and real-time polymerase chain reaction arrays. Autophagy-related protein7 (ATG7) was observed to be downregulated after the knockdown of NDC80 in lung cancer cells. Immunohistochemistry assay results revealed that both NDC80 and ATG7 were upregulated in an array of lung adenocarcinoma samples, compared to normal tissues, and the expression of NDC80 was identified to be positively associated with the levels of ATG7. Our findings suggest that NDC80 promotes the development of lung cancer by regulating autophagy, and might serve as a potential target for increasing the therapeutic sensitivity of lung cancer.

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Aberrant Expression of ADARB1 Facilitates Temozolomide Chemoresistance and Immune Infiltration in Glioblastoma

Cited by 3 publications

References 57 publications

Smurf1 Suppression Enhances Temozolomide Chemosensitivity in Glioblastoma by Facilitating PTEN Nuclear Translocation

Smurf1 Suppression Enhances Temozolomide Chemosensitivity in Glioblastoma by Facilitating PTEN Nuclear Translocation

Abnormally Expressed Ferroptosis-Associated FANCD2 in Mediating the Temozolomide Resistance and Immune Response in Glioblastoma

Upregulation of nuclear division cycle 80 contributes to therapeutic resistance via the promotion of autophagy-related protein-7-dependent autophagy in lung cancer

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