scholarly journals MDM2-dependent Sirt1 degradation is a prerequisite for Sirt6-mediated cell death in head and neck cancers

Author(s):  
Jung Je Park ◽  
Young-Sool Hah ◽  
Somi Ryu ◽  
So Young Cheon ◽  
Seong Jun Won ◽  
...  

AbstractSirt6 is involved in multiple biological processes, including aging, metabolism, and tumor suppression. Sirt1, another member of the sirtuin family, functionally overlaps with Sirt6, but its role in tumorigenesis is controversial. In this study, we focused on cell death in association with Sirt6/Sirt1 and reactive oxygen species (ROS) in head and neck squamous cell carcinomas (HNSCCs). Sirt6 induced cell death, as widely reported, but Sirt1 contributed to cell death only when it was suppressed by Sirt6 via regulation of MDM2. Sirt6 and Sirt6-mediated suppression of Sirt1 upregulated ROS, which further led to HNSCC cell death. These results provide insight into the molecular roles of Sirt6 and Sirt1 in tumorigenesis and could therefore contribute to the development of novel strategies to treat HNSCC.

2008 ◽  
Vol 118 (10) ◽  
pp. 1787-1790 ◽  
Author(s):  
Chikatoshi Katada ◽  
Meijin Nakayama ◽  
Satoshi Tanabe ◽  
Wasaburo Koizumi ◽  
Takashi Masaki ◽  
...  

Immunology ◽  
2009 ◽  
Vol 128 (1pt2) ◽  
pp. e600-e611 ◽  
Author(s):  
Camilla Rydberg ◽  
Anne Månsson ◽  
Rolf Uddman ◽  
Kristian Riesbeck ◽  
Lars-Olaf Cardell

2019 ◽  
Vol 18 (3) ◽  
pp. 273-276
Author(s):  
Lin Ya-Hsuan ◽  
Chiu Valeria ◽  
Huang Chun-Yen ◽  
Tzeng I-Shiang ◽  
Hsieh Po-Chun ◽  
...  

Oral cancer is a type of head and neck cancer that can be life threatening if not diagnosed and treated early. Ferroptosis is a type of programmed or regulated cell death dependent on iron and reactive oxygen species but is a caspase-independent form of non-apoptotic cell death. Therefore, there is a need to identify candidate natural compound that may attenuate carcinogenesis through ferroptosis. To this end, we determined the pharmacological effects of chrysophanol on ferroptosis in two different oral cancer cell lines—FaDu, a hypopharyngeal squamous cell carcinoma and SAS, a poorly differentiated squamous cell carcinoma cell line from human tongue primary lesion. Results indicated that chrysophanol caused overproduction of lipid reactive oxygen species, decreased the level of glutathione peroxidase 4, and increased the level of lipocalin-2 and CCAAT-enhancer-binding protein homologous protein. These findings suggest that chrysophanol has the therapeutic potential to alleviate the progression of oral carcinogenesis through activation of ferroptosis.


2006 ◽  
Vol 132 (8) ◽  
pp. 844
Author(s):  
J. Chad Brenner ◽  
J. A. Bauer ◽  
L. M. Saunders ◽  
K. M. O’Connell ◽  
C. R. Bradford ◽  
...  

2007 ◽  
Vol 104 (18) ◽  
pp. 7540-7545 ◽  
Author(s):  
Shaoyu Zhou ◽  
Sushant Kachhap ◽  
Wenyue Sun ◽  
Guojun Wu ◽  
Alice Chuang ◽  
...  

Mitochondrial genomic mutations are found in a variety of human cancers; however, the frequency of mitochondrial DNA (mtDNA) mutations in coding regions remains poorly defined, and the functional effects of mitochondrial mutations found in primary human cancers are not well described. Using MitoChip, we sequenced the whole mitochondrial genome in 83 head and neck squamous cell carcinomas. Forty-one of 83 (49%) tumors contained mtDNA mutations. Mutations occurred within noncoding (D-loop) and coding regions. A nonrandom distribution of mutations was found throughout the mitochondrial enzyme complex components. Sequencing of margins with dysplasia demonstrated an identical nonconservative mitochondrial mutation (A76T in ND4L) as the tumor, suggesting a role of mtDNA mutation in tumor progression. Analysis of p53 status showed that mtDNA mutations correlated positively with p53 mutations (P < 0.002). To characterize biological function of the mtDNA mutations, we cloned NADH dehydrogenase subunit 2 (ND2) mutants based on primary tumor mutations. Expression of the nuclear-transcribed, mitochondrial-targeted ND2 mutants resulted in increased anchorage-dependent and -independent growth, which was accompanied by increased reactive oxygen species production and an aerobic glycolytic metabolic phenotype with hypoxia-inducible factor (HIF)-1α induction that is reversible by ascorbate. Cancer-specific mitochondrial mutations may contribute to development of a malignant phenotype by direct genotoxic effects from increased reactive oxygen species production as well as induction of aerobic glycolysis and growth promotion.


2014 ◽  
Vol 42 (1) ◽  
pp. 47-51 ◽  
Author(s):  
Julea N. Butt

Apoptosis is triggered by an accumulation of ROS (reactive oxygen species) produced by proteins of the mitochondrial respiratory chain. The levels of ROS are controlled by the activities of mitochondrial redox proteins such as glutaredoxin 2 that help to modulate the susceptibility of a cell to apoptosis. However, once downstream events have resulted in the release of cytochrome c to the cytosol, it is widely considered that cell death is inevitable. Cytochrome c may promote its own release from mitochondria through interactions with the mitochondrial phospholipid cardiolipin (diphosphatidylglycerol). In the present article, spectroelectrochemistry of the cardiolipin complex of cytochrome c and protein film electrochemistry of glutaredoxin 2 are reviewed to illustrate how electrochemical methods provide insight into the properties of signalling proteins.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yi An ◽  
Jun Jeon ◽  
Lillian Sun ◽  
Adeeb Derakhshan ◽  
Jianhong Chen ◽  
...  

AbstractHead and neck squamous cell carcinomas (HNSCC) induced by human papillomavirus (HPV) have increased recently in the US. However, the distinct alterations of molecules involved in the death pathways and drug effects targeting inhibitor of apoptosis proteins (IAPs) have not been extensively characterized in HPV(+) HNSCC cells. In this study, we observed the distinct genomic and expression alterations of nine genes involved in cell death in 55% HNSCC tissues, which were associated with HPV status, tumor staging, and anatomic locations. Expression of four genes was statistically correlated with copy number variation. A panel of HPV(+) HNSCC lines showed abundant TRAILR2 and IAP1 protein expression, but were not sensitive to IAP inhibitor birinapant alone, while combinatory treatment with TNFα or especially TRAIL enhanced this drug sensitivity. The death agonistic TRAILR2 antibody alone showed no cell inhibitory effects, whereas its combination with birinapant and/or TRAIL protein demonstrated additive or synergistic effects. We observed predominantly late apoptosis mode of cell death after combinatorial treatments, and pan-caspase (ZVAD) and caspase-8 (ZIETD) inhibitors attenuated treatment-induced cell death. Our genomic and expression data-driven study provides a framework for identifying relevant combinatorial therapies targeting death pathways in HPV(+) HNSCC and other squamous cancer types.


2000 ◽  
Vol 114 (10) ◽  
pp. 772-776 ◽  
Author(s):  
J. S. Rubin ◽  
B. K. Bloor ◽  
I. R. Hart ◽  
P. R. Morgan

Polymorphic epithelial mucin (PEM), the protein product of the gene muc-1, is a surface glycoprotein that is produced by a range of normal epithelial cells, but has been shown to be expressed at high levels in a range of adenocarcinomas. It has not been investigated extensively in head and neck related tissues, and not at all in head and neck squamous cell carcinomas (HNSCC). This immunohistochemical investigation using two monoclonal antibodies to muc-1 represents a baseline study of 18 HNSCC. In 13 cases, the glycoprotein was expressed at varying levels, usually in keratinizing foci. Although less prominent, expression was also present to some degree in nine of 23 control specimens of non-neoplastic mucosa, mostly at an epithelial level early in the parakeratinization process. Both antibodies showed a pattern of staining. The cellular basis for muc-1 expression is speculative at present and although it is at a lower level than in adenocarcinomas, it may help to provide further insight into epithelial cell differentiation in squamous cell carcinomas.


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