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AR ubiquitination induced by the curcumin analog suppresses growth of temozolomide-resistant glioblastoma through disrupting GPX4-Mediated redox homeostasis.

ABSTRACT: Drug resistance is the main obstacle in the improvement of chemotherapeutic efficacy in glioblastoma. Previously, we showed that dehydroepiandrosterone (DHEA), one kind of androgen/neurosteroid, potentiates glioblastoma to acquire resistance through attenuating DNA damage. Androgen receptor (AR) activated by DHEA or other types of androgen was reported to promote drug resistance in prostate cancer. However, in DHEA-enriched microenvironment, the role of AR in acquiring resistance of glioblastoma remains unknown. In this study, we found that AR expression is significantly correlated with poor prognosis, and AR obviously induced the resistance to temozolomide (TMZ) treatment. Herein, we observed that ALZ003, a curcumin analog, induces FBXL2-mediated AR ubiquitination, leading to degradation. Importantly, ALZ003 significantly inhibited the survival of TMZ-sensitive and -resistant glioblastoma in vitro and in vivo. The accumulation of reactive oxygen species (ROS), lipid peroxidation and suppression of glutathione peroxidase (GPX) 4, which are characteristics of ferroptosis, were observed in glioblastoma cell after treatment of ALZ003. Furthermore, overexpression of AR prevented ferroptosis in the presence of GPX4. To evaluate the therapeutic effect in vivo, we transplanted TMZ-sensitive or -resistant U87MG cells into mouse brain followed by intravenous administration with ALZ003. In addition to inhibiting the growth of glioblastoma, ALZ003 significantly extended the survival period of transplanted mice, and significantly decreased AR expression in the tumor area. Taken together, AR potentiates TMZ resistance for glioblastoma, and ALZ003-mediated AR ubiquitination might open a new insight into therapeutic strategy for TMZ resistant glioblastoma.

SUBMITTER: Chen TC

PROVIDER: S-EPMC6940696 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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AR ubiquitination induced by the curcumin analog suppresses growth of temozolomide-resistant glioblastoma through disrupting GPX4-Mediated redox homeostasis.

Chen Tzu-Chi TC Chuang Jian-Ying JY Ko Chiung-Yuan CY Kao Tzu-Jen TJ Yang Pei-Yu PY Yu Chun-Hui CH Liu Ming-Sheng MS Hu Siou-Lian SL Tsai Yu-Ting YT Chan Hardy H Chang Wen-Chang WC Hsu Tsung-I TI

Redox biology 20191226

Drug resistance is the main obstacle in the improvement of chemotherapeutic efficacy in glioblastoma. Previously, we showed that dehydroepiandrosterone (DHEA), one kind of androgen/neurosteroid, potentiates glioblastoma to acquire resistance through attenuating DNA damage. Androgen receptor (AR) activated by DHEA or other types of androgen was reported to promote drug resistance in prostate cancer. However, in DHEA-enriched microenvironment, the role of AR in acquiring resistance of glioblastoma ...[more]

PMID: 31896509

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Project description:Background:LncRNAs have been shown to play essential roles in cancer therapeutic response. However, the detailed mechanism of lncRNAs in temozolomide (TMZ) resistance in glioblastoma (GBM) remain to be elucidated. Methods:To elucidate the mechanism maintaining TMZ resistance, we constructed two TMZ-resistant GBM cell lines (T98G-R/U118-R). LncRNAs from four public datasets were reanalyzed, and the candidate lncRNA ADAMTS9-AS2 was evaluated in TMZ-treated GBM patients and in vitro cell lines. Results:Reanalysis of lncRNA expression profiles identified ADAMTS9-AS2 as significantly overexpressed in TMZ-resistant GBM cells and as positively associated with the IC50 of TMZ in GBM cells. Overexpression of ADAMTS9-AS2 was also significantly associated with poor TMZ response and shorter progression-free survival (PFS) in TMZ-treated GBM patients. Knockdown of ADAMTS9-AS2 inhibited proliferation and attenuated the IC50 of TMZ, as well as mitigating invasion and migration in TMZ-resistant GBM cells. Subsequent investigations indicated that reduced expression of ADAMTS9-AS2 significantly suppressed expression of the FUS protein, which was predicted as a direct substrate of ADAMTS9-AS2. Expression trends of FUS were directly correlated with those of ADAMTS9-AS2, as shown by increasing concentrations and prolonged treatment with TMZ. RNA pull-down and RIP assays indicated that both endogenous and exogenous ADAMTS9-AS2 directly binds to the RRM and Znf_RanBP2 domains of FUS, consequently increasing FUS protein expression. Knockdown of ADAMTS9-AS2 reduced the half-life of FUS and decreased FUS protein stability via K48 ubiquitin degradation. Moreover, the E3 ubiquitin-protein ligase MDM2 interacts with and down regulates FUS, while the RRM and Znf_RanBP2 domains of FUS facilitate its binding with MDM2. ADAMTS9-AS2 decreased the interaction between MDM2 and FUS, which mediates FUS K48 ubiquitination. Additionally, knockdown of the ADAMTS9-AS2/FUS signaling axis significantly alleviated progression and metastasis in TMZ-resistant cells. Conclusion:ADAMTS9-AS2 possessed a novel function that promotes TMZ resistance via upregulating the FUS/MDM2 axis in GBM cells. The RRM or Znf_RanBP2 domains of FUS facilitate the combination of ADAMTS9-AS2 and FUS, competitively inhibiting MDM2-dependent FUS K48 ubiquitination and resulting in enhanced FUS stability and TMZ resistance. Our results suggest that the ADAMTS9-AS2/FUS/MDM2 axis may represent a suitable prognostic biomarker and a potential target in TMZ-resistant GBM therapy.

Dataset Information

AR ubiquitination induced by the curcumin analog suppresses growth of temozolomide-resistant glioblastoma through disrupting GPX4-Mediated redox homeostasis.

Publications

AR ubiquitination induced by the curcumin analog suppresses growth of temozolomide-resistant glioblastoma through disrupting GPX4-Mediated redox homeostasis.

Similar Datasets

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