scholarly journals An Experimentally Induced Mutation in the UBA Domain of p62 Changes the Sensitivity of Cisplatin by Up-Regulating HK2 Localisation on the Mitochondria and Increasing Mitophagy in A2780 Ovarian Cancer Cells

2021 ◽  
Vol 22 (8) ◽  
pp. 3983
Author(s):  
Sihang Yu ◽  
Xiaoyu Yan ◽  
Rui Tian ◽  
Long Xu ◽  
Yuanxin Zhao ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Treatment ◽  
Cell Survival ◽  
Cancer Cells ◽  
Treatment Strategies ◽  
Ovarian Cancer Cells ◽  
Induced Mutation ◽  
Uba Domain ◽  
Cisplatin Sensitivity ◽  
Experimentally Induced

The study of cisplatin sensitivity is the key to the development of ovarian cancer treatment strategies. Mitochondria are one of the main targets of cisplatin, its self-clearing ability plays an important role in determining the fate of ovarian cancer cells. First, we proved that the sensitivity of ovarian cancer cells to cisplatin depends on mitophagy, and p62 acts as a broad autophagy receptor to regulate this process. However, p62′s regulation of mitophagy does not depend on its location on the mitochondria. Our research shows that the mutation of the UBA domain of p62 increases the localisation of HK2 on the mitochondria, thereby increasing the phosphorylated ubiquitin form of parkin, then stabilising the process of mitophagy and ultimately cell survival. Collectively, our results showed that a mutation in the UBA domain of p62 regulates the level of apoptosis stimulated by cisplatin in ovarian cancer.

scholarly journals Promotion of Cell Death in Cisplatin-Resistant Ovarian Cancer Cells through KDM1B-DCLRE1B Modulation

2019 ◽  
Vol 20 (10) ◽  
pp. 2443 ◽  
Author(s):  
Yeon Kyu Lee ◽  
Jinyeong Lim ◽  
So Young Yoon ◽  
Jong Cheon Joo ◽  
Soo Jung Park ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Ovarian Cancer Cells ◽  
Repair Gene ◽  
Gynecological Malignancy ◽  
Downstream Target ◽  
Dna Repair Gene ◽  
Cisplatin Sensitivity

Ovarian cancer is the gynecological malignancy with the poorest prognosis, in part due to its high incidence of recurrence. Platinum agents are widely used as a first-line treatment against ovarian cancer. Recurrent tumors, however, frequently demonstrate acquired chemo-resistance to platinum agent toxicity. To improve chemo-sensitivity, combination chemotherapy regimens have been investigated. This study examined anti-tumor effects and molecular mechanisms of cytotoxicity of Oldenlandia diffusa (OD) extracts on ovarian cancer cells, in particular, cells resistant to cisplatin. Six ovarian cancer cells including A2780 and cisplatin-resistant A2780 (A2780cis) as representative cell models were used. OD was extracted with water (WOD) or 50% methanol (MOD). MOD significantly induced cell death in both cisplatin-sensitive cells and cisplatin-resistant cells. The combination treatment of MOD with cisplatin reduced viability in A2780cis cells more effectively than treatment with cisplatin alone. MOD in A2780cis cells resulted in downregulation of the epigenetic modulator KDM1B and the DNA repair gene DCLRE1B. Transcriptional suppression of KDM1B and DCLRE1B induced cisplatin sensitivity. Knockdown of KDM1B led to downregulation of DCLRE1B expression, suggesting that DCLRE1B was a KDM1B downstream target. Taken together, OD extract effectively promoted cell death in cisplatin-resistant ovarian cancer cells under cisplatin treatment through modulating KDM1B and DCLRE1B.

scholarly journals Wild-Type Tumor Repressor Protein 53 (TRP53) Promotes Ovarian Cancer Cell Survival

Endocrinology ◽  
2012 ◽  
Vol 153 (4) ◽  
pp. 1638-1648 ◽  
Author(s):  
Lisa K. Mullany ◽  
Zhilin Liu ◽  
Erin R. King ◽  
Kwong-Kwok Wong ◽  
JoAnne S. Richards
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Ovarian Cancer ◽  
Dna Repair ◽  
Cell Survival ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Low Grade ◽  
Wild Type ◽  
Repressor Protein

Loss of Pten in the KrasG12D;Amhr2-Cre mutant mice leads to the transformation of ovarian surface epithelial (OSE) cells and rapid development of low-grade, invasive serous adenocarcinomas. Tumors occur with 100% penetrance and express elevated levels of wild-type tumor repressor protein 53 (TRP53). To test the functions of TRP53 in the Pten;Kras (Trp53+) mice, we disrupted the Trp53 gene yielding Pten;Kras(Trp53−) mice. By comparing morphology and gene expression profiles in the Trp53+ and Trp53− OSE cells from these mice, we document that wild-type TRP53 acts as a major promoter of OSE cell survival and differentiation: cells lacking Trp53 are transformed yet are less adherent, migratory, and invasive and exhibit a gene expression profile more like normal OSE cells. These results provide a new paradigm: wild-type TRP53 does not preferentially induce apoptotic or senescent related genes in the Pten;Kras(Trp53+) cancer cells but rather increases genes regulating DNA repair, cell cycle progression, and proliferation and decreases putative tumor suppressor genes. However, if TRP53 activity is forced higher by exposure to nutlin-3a (a mouse double minute-2 antagonist), TRP53 suppresses DNA repair genes and induces the expression of genes that control cell cycle arrest and apoptosis. Thus, in the Pten;Kras(Trp53+) mutant mouse OSE cells and likely in human TP53+ low-grade ovarian cancer cells, wild-type TRP53 controls global molecular changes that are dependent on its activation status. These results suggest that activation of TP53 may provide a promising new therapy for managing low-grade ovarian cancer and other cancers in humans in which wild-type TP53 is expressed.

scholarly journals Aurora-A induces cell survival and chemoresistance by activation of Akt through a p53-dependent manner in ovarian cancer cells

2006 ◽  
Vol 119 (10) ◽  
pp. 2304-2312 ◽  
Author(s):  
Hua Yang ◽  
Lili He ◽  
Patricia Kruk ◽  
Santo V. Nicosia ◽  
Jin Q. Cheng
Keyword(s):  
Ovarian Cancer ◽  
Cell Survival ◽  
Cancer Cells ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Aurora A
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