MUS81 is associated with cell proliferation and cisplatin sensitivity in serous ovarian cancer

Xie, Shuanshuan; Zheng, Hui; Wen, Xiaoyan; Sun, Jin; Wang, Yanchun; Gao, Xiang; Guo, Lin; Lu, Renquan

doi:10.1016/j.bbrc.2016.05.152

Cited by 23 publications

(30 citation statements)

References 26 publications

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“…Patients with ovarian cancer usually respond well to initial chemotherapy with cisplatin. However, most patients develop resistance to cisplatin during the course of their treatment ( 1 , 19 ). Hence, there is an urgent need to identify new therapeutic targets in ovarian cancer and to develop novel, potent and specific drugs.…”

Section: Discussionmentioning

confidence: 99%

“…Ovarian cancer, the seventh most common cancer among women, remains one of the leading causes of cancer-associated morbidity and mortality. It has become the third most common cancer of female genital organs, after cervical cancer and endometrial cancer ( 1 , 2 ). cis -Dichlorodiammineplatinum (II) (cisplatin) has been the standard of care against ovarian cancer for several decades.…”

Section: Introductionmentioning

confidence: 99%

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BMH-21 inhibits viability and induces apoptosis by p53-dependent nucleolar stress responses in SKOV3 ovarian cancer cells

Ling

et al. 2017

Oncology Reports

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The nucleolus is a stress sensor associated with cell cycle progression and apoptosis. Studies have shown that nucleolar stress is positively correlated with apoptosis in breast, prostate and lung cancer cells. However, the role and function of nucleolar stress in ovarian cancer has not been reported. In this study, we found that the nucleolar stress inducer BMH-21 inhibited viability of SKOV3 ovarian cancer cells in a dose-dependent manner. Furthermore, BMH-21 induced the expression of nucleolar stress marker proteins (nucleolin, nucleophosmin and fibrillarin) and promoted the nuclear export of these proteins. BMH-21 also decreased MDM2 proto-oncogene expression and increased protein levels of the tumor suppressor p53 and p53 phosphorylated at serine 15 (p-p53-Ser15), which contributed to increased expression of the downstream apoptosis-related protein BCL2 associated X (BAX) and activation of caspase-3. Taken together, these data provide the first reported evidence that induction of p53-dependent nucleolar stress by BMH-21 induces apoptosis in ovarian cancer. Our data suggest that nucleolar stress might be a pathway suitable for targeting in ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BMH-21 inhibits viability and induces apoptosis by p53-dependent nucleolar stress responses in SKOV3 ovarian cancer cells

Ling

et al. 2017

Oncology Reports

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“…The cells were irradiated with different degrees of ultraviolet radiation using a UV cross-linking instrument. The irradiation degree was calculated as number x area x 1x10 6 . Protein was extracted using the same method and verified with western blotting.…”

Section: Methodsmentioning

confidence: 99%

“…Changes in HJs affect both the activity and DNA stability of homologous recombination (HR) in the repair of DSBs. Our previous studies demonstrated that downregulation of MUS81 inhibits ovarian tumor growth and enhances platinum drug sensitivity both in vivo and in vitro (6). Moreover, MUS81-targeting represents a novel approach for promoting sensitivity to chemotherapy and has recently attracted significant research attention.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of MUS81 improves the chemical sensitivity of olaparib by regulating MCM2 in epithelial ovarian cancer

et al. 2018

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Dysfunction of the DNA repair pathway contributes to tumorigenesis and drug resistance. Methyl methanesulfonate and ultraviolet sensitive gene clone 81 (MUS81), a key endonuclease in DNA repair, is generally considered a tumor suppressor; however, recent studies have revealed its tumor-promoting effect in epithelial ovarian cancer (EOC) and have shown that its overexpression is associated with cisplatin sensitization. However, the exact functional role of MUS81 and its regulation in relation to chemotherapy sensitivity remains unknown. Our previous study using protein interaction chip revealed that minichromosome maintenance complex component 2 (MCM2) is closely correlated with MUS81. This study aimed to investigate the biological effects and mechanisms of MUS81 on cellular responses to chemotherapeutic drugs. To accomplish this, we downregulated MUS81 and MCM2 in A2780 and SKOV3 ovarian cancer cells using lentivirus-mediated RNAi. Using a qPCR-based HR assay kit to detect HR efficiency. The sensitivity of MUS81 to olaparib was investigated by cell proliferation, colony formation assays and flow cytometry. The results showed that MUS81 modulates MCM2 levels as well as homologous recombination (HR) activity. Moreover, downregulation of MUS81 increased the sensitivity of EOC cells to olaparib by inducing S phase arrest and promoting apoptosis through activation of MCM2. MUS81 may be a potential novel therapeutic target for EOC.

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“…The MUS81 protein acts in 3 -flap stalled replication fork [41], Holliday structure [42], which prevents chromosomal breaks and deleterious recombination [43,44]. Deregulated expression of MUS81 was reported in serous ovarian [45] and prostate [46] cancer cells. In hepatocellular [47] and BC cells [48], depletion of MUS81 increased chemosensitivity, highlighting a potential target for cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Germline Mutation in MUS81 Resulting in Impaired Protein Stability is Associated with Familial Breast and Thyroid Cancer

Pinheiro

Lupinacci

Santiago

et al. 2020

Cancers

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Multiple primary thyroid cancer (TC) and breast cancer (BC) are commonly diagnosed, and the lifetime risk for these cancers is increased in patients with a positive family history of both TC and BC. Although this phenotype is partially explained by TP53 or PTEN mutations, a significant number of patients are negative for these alterations. We judiciously recruited patients diagnosed with BC and/or TC having a family history of these tumors and assessed their whole-exome sequencing. After variant prioritization, we selected MUS81 c.1292G>A (p.R431H) for further investigation. This variant was genotyped in a healthy population and sporadic BC/TC tissues and investigated at the protein level and cellular models. MUS81 c.1292G>A was the most frequent variant (25%) and the strongest candidate due to its function of double-strand break repair. This variant was confirmed in four relatives from two families. MUS81 p.R431H protein exhibited lower expression levels in tumors from patients positive for the germline variant, compared with wild-type BC, and normal breast and thyroid tissues. Using cell line models, we showed that c.1292G>A induced protein instability and affected DNA damage response. We suggest that MUS81 is a novel candidate involved in familial BC/TC based on its low frequency in healthy individuals and proven effect in protein stability.

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MUS81 is associated with cell proliferation and cisplatin sensitivity in serous ovarian cancer

Cited by 23 publications

References 26 publications

BMH-21 inhibits viability and induces apoptosis by p53-dependent nucleolar stress responses in SKOV3 ovarian cancer cells

BMH-21 inhibits viability and induces apoptosis by p53-dependent nucleolar stress responses in SKOV3 ovarian cancer cells

Inhibition of MUS81 improves the chemical sensitivity of olaparib by regulating MCM2 in epithelial ovarian cancer

Germline Mutation in MUS81 Resulting in Impaired Protein Stability is Associated with Familial Breast and Thyroid Cancer

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