Parkin Regulates Mitosis and Genomic Stability through Cdc20/Cdh1

Lee, Seung Baek; Kim, Jung Jin; Nam, Hyun Ja; Gao, Bowen; Yin, Ping; Qin, Bo; Yi, Sang Yeop; Ham, Hyoungjun; Evans, Debra L.; Kim, Sun Hyun; Zhang, Jun; Deng, Min; Liu, Tongzheng; Zhang, Haoxing; Billadeau, Daniel D.; Wang, Liewei; Giaime, Emilie; Shen, Jie; Pang, Yuan Ping; Jen, Jin; Deursen, Jan M. van; Lou, Zhenkun

doi:10.1016/j.molcel.2015.08.011

Cited by 80 publications

(111 citation statements)

References 48 publications

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“…13 Parkin-Cdc20/Cdh1 complex deficiency results in mitotic defects and genomic instability. 23 Genomic instability, resulting in extensive DNA and chromosomal variations, is believed to be a driving force in carcinogenesis. 24 Genomic instability occurred frequently in most of the cancers.…”

Section: Introductionmentioning

confidence: 99%

Inactivation of parkin by promoter methylation correlated with lymph node metastasis and genomic instability in nasopharyngeal carcinoma

Zhou

Yuan

et al. 2017

Tumour Biol.

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This study aimed to investigate the inactivation of the parkin gene by promoter methylation and its relationship with genome instability in nasopharyngeal carcinoma. Parkin was considered as a tumor suppressor gene in various types of cancers. However, its role in nasopharyngeal carcinoma is unexplored. Genomic instabilities were detected in nasopharyngeal carcinoma tissues by the random amplified polymorphic DNA. The methylation-specific polymerase chain reaction, semi-quantitative reverse transcription polymerase chain reaction, and immunohistochemical analysis were used to detect methylation and mRNA and protein expression of parkin in 54 cases of nasopharyngeal carcinoma tissues and 16 cases of normal nasopharyngeal epithelia tissues, and in 5 nasopharyngeal carcinoma cell lines (CNE1, CNE2, TWO3, C666, and HONE1) and 1 normal nasopharyngeal epithelia cell line (NP69). mRNA expression of parkin in CNE1 and CNE2 was analyzed before and after methyltransferase inhibitor 5-aza-2-deoxycytidine treatment. The relationship between promoter methylation and mRNA expression, demethylation and mRNA expression, and mRNA and protein expression of the gene and clinical factors and genomic instabilities were analyzed. The mRNA and protein expression levels were significantly reduced in 54 cases of human nasopharyngeal carcinoma compared with 16 cases of normal nasopharyngeal epithelia. Parkin-methylated cases showed significantly lower mRNA and protein expression levels compared with unmethylated cases. After 5-aza-2-deoxycytidine treatment, parkin mRNA expression was restored in CNE1 and CNE2; 92.59% (50/54) of nasopharyngeal carcinoma demonstrated genomic instability. Parkin is frequently inactivated by promoter methylation, and its mRNA and protein expression correlate with lymph node metastasis and genomic instability. Parkin deficiency probably promotes tumorigenesis in nasopharyngeal carcinoma.

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Section: Introductionmentioning

confidence: 99%

Inactivation of parkin by promoter methylation correlated with lymph node metastasis and genomic instability in nasopharyngeal carcinoma

Zhou

Yuan

et al. 2017

Tumour Biol.

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“…Similarly, PINK1 was shown to suppress ROS generation, HIF-1 stabilization and the Warburg effect in human astrocytes [35]. However, the role of Parkin in cancer is complicated by more recent findings showing that it regulates cyclin levels and exit from mitosis [41,42]. As a component of the FBX4 Cullin-ring ligase complex, Parkin regulates levels of Cyclin D1, Cyclin E, and CDK4 in cancers [41].…”

Section: Mechanics Of Mitophagy and Key Mitophagy Proteinsmentioning

confidence: 99%

“…As a component of the FBX4 Cullin-ring ligase complex, Parkin regulates levels of Cyclin D1, Cyclin E, and CDK4 in cancers [41]. Additionally, through its ability to bind Cdc20 and substitute for the Anaphase promoting complex (APC), Parkin also modulates mitotic checkpoint control and Parkin loss subsequently leads to chromosomal instability and aneuploidy [42]. Thus, it is unclear whether the tumor suppressor activity of Parkin relates to its role in mitophagy or to its role in cell cycle.…”

Section: Mechanics Of Mitophagy and Key Mitophagy Proteinsmentioning

confidence: 99%

Expanding perspectives on the significance of mitophagy in cancer

Drake

Springer

Poole

et al. 2017

Seminars in Cancer Biology

145

116

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Mitophagy is a selective mode of autophagy in which mitochondria are specifically targeted for degradation at the autophagolysosome. Mitophagy is activated by stresses such as hypoxia, nutrient deprivation, DNA damage, inflammation and mitochondrial membrane depolarization and plays a role in maintaining mitochondrial integrity and function. Defects in mitophagy lead to mitochondrial dysfunction that can affect metabolic reprogramming in response to stress, alter cell fate determination and differentiation, which in turn affects disease incidence and etiology, including cancer. Here, we discuss how different mitophagy adaptors and modulators, including Parkin, BNIP3, BNIP3L, p62/SQSTM1 and OPTN, are regulated in response to physiological stresses and deregulated in cancers. Additionally, we explore how these different mitophagy control pathways coordinate with each other. Finally, we review new developments in understanding how mitophagy affects stemness, cell fate determination, inflammation and DNA damage responses that are relevant to understanding the role of mitophagy in cancer.

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“…Pink1 phosphorylates the ubiquitinlike domain of Parkin at serine 65 to activate its E3 ligase activity, which is involved in mitophagy [20,21] . Recently, PLK1 was reported to interact with the C-terminal region of Parkin and phosphorylate S378, which results in a dramatic enhancement of its E3 ligase activity [22] . This prompted us to explore To analyze the effects of TL-2-8 on autophagy, the expression levels of autophagy-related proteins in TL-2-8-treated breast cancer cells were investigated by Western blotting.…”

Section: Tl-2-8-induced Immature Mitophagymentioning

confidence: 99%

The flavonoid TL-2-8 induces cell death and immature mitophagy in breast cancer cells via abrogating the function of the AHA1/Hsp90 complex

et al. 2017

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The flavonoid quercetin exhibits significant anticancer activities with few side effects. In the current study, we characterized TL-2-8, a quercetin derivative, as a novel anticancer agent in vitro and in vivo. Cell proliferation and viability were assessed using Cell Counting Kit-8 and CellTiter-Blue assay, respectively. Cell death was examined using PI staining or a TUNEL assay. Mitophagy was determined by measuring autophagic flux and by confocal imaging. Protein expression was examined by Western blotting. We found that TL-2-8 selectively inhibited the proliferation and decreased the viability of various cancer cells (the anti-proliferation IC 50 values in MDA-MB-231, MDA-MB-468 and MCF-7 breast cancer cells at 72 h were 8.28, 8.56, and 9.58 μmol/L, respectively), and it displayed only slight cytotoxicity against normal MCF-10A and HEK-293 cells. In MDA-MB-231 and MDA-MB-468 breast cancer cells, TL-2-8 treatment induced the degradation of multiple Hsp90 client proteins without inducing Hsp70. TL-2-8 (3, 6, 12 μmol/L) dose-dependently inhibited the expression of AHA1, an activator of Hsp90 ATPase, and decreased Hsp90-AHA1 complex formation, leading to decreased Hsp90 chaperone function and reduced polo-like kinase 1 (PLK1) signaling. Consequently, impaired mitophagy was induced via the downregulation of lysosomal-associated membrane protein 2 (LAMP2). The in vivo anticancer effects of TL-2-8 were evaluated in an MDA-MB-231 breast cancer xenograft model, which was treated with TL-2-8 (25, 50, 100 mg·kg -1 ·d -1 , po). Administration of TL-2-8 resulted in tumor growth inhibition rates of 37.9%, 58.9% and 70.9%, respectively, whereas quercetin treatment (100 mg·kg -1 ·d -1 , po) produced only a lower tumor growth inhibition rate (49.5%). Furthermore, TL-2-8 treatment significantly extended the lifespan of mice bearing MDA-MB-231 breast cancer cell xenografts. Our results demonstrate that TL-2-8 induces significant cell death and immature mitophagy in breast cancer cells in vitro and in vivo via AHA1 abrogation.

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Parkin Regulates Mitosis and Genomic Stability through Cdc20/Cdh1

Cited by 80 publications

References 48 publications

Inactivation of parkin by promoter methylation correlated with lymph node metastasis and genomic instability in nasopharyngeal carcinoma

Inactivation of parkin by promoter methylation correlated with lymph node metastasis and genomic instability in nasopharyngeal carcinoma

Expanding perspectives on the significance of mitophagy in cancer

The flavonoid TL-2-8 induces cell death and immature mitophagy in breast cancer cells via abrogating the function of the AHA1/Hsp90 complex

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