ARID1A ablation leads to multiple drug resistance in ovarian cancer via transcriptional activation of MRP2

Luo, Qingyu; Wu, Xiaowei; Zhang, Yiping; Shu, Tong; Ding, Fang; Chen, Hongyan; Zhao, Pengfei; Chang, Wan; Zhu, Xiaolin; Liu, Zhihua

doi:10.1016/j.canlet.2018.04.013

Cited by 38 publications

(24 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Informed consent was obtained from all patients, and tissue samples were de-identified before use. IHC experiments were performed as previously described (33). All slides were scanned using an Aperio scanning system (Aperio).…”

Section: Methodsmentioning

confidence: 99%

MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer

Luo

Zhao

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Chemoresistance is a severe outcome among patients with ovarian cancer that leads to a poor prognosis. MCL1 is an antiapoptotic member of the BCL-2 family that has been found to play an essential role in advancing chemoresistance and could be a promising target for the treatment of ovarian cancer. Here, we found that deubiquitinating enzyme 3 (DUB3) interacts with and deubiquitinates MCL1 in the cytoplasm of ovarian cancer cells, which protects MCL1 from degradation. Furthermore, we identified that O6-methylguanine-DNA methyltransferase (MGMT) is a key activator of DUB3 transcription, and that the MGMT inhibitor PaTrin-2 effectively suppresses ovarian cancer cells with elevated MGMT-DUB3-MCL1 expression both in vitro and in vivo. Most interestingly, we found that histone deacetylase inhibitors (HDACis) could significantly activate MGMT/DUB3 expression; the combined administration of HDACis and PaTrin-2 led to the ideal therapeutic effect. Altogether, our results revealed the essential role of the MGMT-DUB3-MCL1 axis in the chemoresistance of ovarian cancer and identified that a combined treatment with HDACis and PaTrin-2 is an effective method for overcoming chemoresistance in ovarian cancer.

show abstract

Section: Methodsmentioning

confidence: 99%

MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer

Luo

Zhao

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Paclitaxel-and platinum-based therapy have been long recommended as the cornerstone for the primary management of ovarian cancer (7)(8)(9). However, the occurrence of multi-drug resistance (MDR) in ovarian cancer has greatly limited therapeutic efficiency of anti-cancer drugs including paclitaxel, carboplatin and cisplatin, ultimately leading to treatment failure (10)(11)(12). Therefore, it is urgent to understand the mechanism involved and thus overcome MDR for successful therapy of ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

Heat Shock Protein 90 Triggers Multi-Drug Resistance of Ovarian Cancer via AKT/GSK3β/β-Catenin Signaling

et al. 2021

View full text Add to dashboard Cite

Ovarian cancer is the most lethal gynaecologic tumor, with which multi-drug resistance as the major therapeutic hindrance. Heat shock protein 90 (Hsp90) has been involved in cancer malignant behaviors. However, its role and mechanism in multi-drug resistance of ovarian cancer remains poorly understood. Our results demonstrated that Hsp90 was overexpressed in multi-drug resistant ovarian cancer cells. Hsp90 downregulation by shHsp90 or inhibitor BIIB021 increased the sensitivity of multi-drug resistant ovarian cancer cells to paclitaxel and cisplatin, and augmented the drugs-induced apoptosis. Hsp90 positively regulated the expressions of multi-drug resistance protein 1 (P-gp/MDR1), breast cancer resistance protein (BCRP), Survivin and Bcl-2 expressions closely associated with multi-drug resistance. Moreover, overexpression of Hsp90 promoted β-catenin accumulation, while Hsp90 downregulation decreased the accumulation, nuclear translocation and transcriptional activity of β-catenin. We also identified that β-catenin was responsible for Hsp90-mediated expressions of P-gp, BCRP, Survivin, and Bcl-2. Furthermore, Hsp90 enhanced the AKT/GSK3β signaling, and AKT signaling played a critical role in Hsp90-induced accumulation and transcriptional activity of β-catenin, as well as multi-drug resistance to paclitaxel and cisplatin. In conclusion, Hsp90 enhanced the AKT/GSK3β/β-catenin signaling to induce multi-drug resistance of ovarian cancer. Suppressing Hsp90 chemosensitized multi-drug resistant ovarian cancer cells via impairing the AKT/GSK3β/β-catenin signaling, providing a promising therapeutic strategy for a successful treatment of ovarian cancer.

show abstract

“…Chemotherapy is one of the most widely applied treatments for cancer in humans, and chemoresistance is one of the most severe obstacles that cancer patients face. Apoptosis escape is considered a hallmark of cancer 11 , contributing to the resistance of cancer cells to both chemotherapy 12 , 13 and radiotherapy 14 . Due to the regulatory role of the BCL-2 family in apoptotic signaling, studies of the BCL-2 family have elucidated the mechanisms underlying chemoresistance and provided several promising therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Ubiquitination and deubiquitination of MCL1 in cancer: deciphering chemoresistance mechanisms and providing potential therapeutic options

Luo

Liu

2020

Cell Death Dis

Self Cite

View full text Add to dashboard Cite

MCL1 is an important antiapoptotic member of the BCL-2 family that is distinguishable from other family members based on its relatively short half-life. Emerging studies have revealed the crucial role of MCL1 in the chemoresistance of cancer cells. The antiapoptotic function of MCL1 makes it a popular therapeutic target, although specific inhibitors have begun to emerge only recently. Notably, emerging studies have reported that several E3 ligases and deubiquitinases modulate MCL1 stability, providing an alternate means of targeting MCL1 activity. In addition, the emergence and development of proteolysis-targeting chimeras, the function of which is based on ubiquitination-mediated degradation, has shown great potential. In this review, we provide an overview of the studies investigating the ubiquitination and deubiquitination of MCL1, summarize the latest evidence regarding the development of therapeutic strategies targeting MCL1 in cancer treatment, and discuss the promising future of targeting MCL1 via the ubiquitin–proteasome system in clinical practice.

show abstract

ARID1A ablation leads to multiple drug resistance in ovarian cancer via transcriptional activation of MRP2

Cited by 38 publications

References 28 publications

MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer

MGMT-activated DUB3 stabilizes MCL1 and drives chemoresistance in ovarian cancer

Heat Shock Protein 90 Triggers Multi-Drug Resistance of Ovarian Cancer via AKT/GSK3β/β-Catenin Signaling

Ubiquitination and deubiquitination of MCL1 in cancer: deciphering chemoresistance mechanisms and providing potential therapeutic options

Contact Info

Product

Resources

About