Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis

Lü, Jianxin; Sharma, Lokendra; Bai, Yidong

doi:10.1038/cr.2009.69

Cited by 240 publications

(205 citation statements)

References 189 publications

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“…These cell lines provide a model system in which we can understand the molecular mechanisms involved to become adapted to NO. In addition, we have adapted a number of tumor cell line pairs arising from other anatomical sites [9,13,40,41] and have studied both cell line pairs using a number of cellular and molecular methods including: MTT viability assay, FACS, LDH leakage assay, DNA sequencing, DNA fragments cloning, qPCR, and Western blot analysis.…”

Section: Discussionmentioning

confidence: 99%

“…The mutation caused a substitution of an amino acid residue from leucine (L) to phenylalanine (F) in exon 6 of p53 gene reported decrease of mtDNA copy number of the HNO cells, when compared with the parent cells, suggests a mitochondrial "malignancy" in the tumor cell [8]. Previous works have linked mtDNA damage with cancer development, progression, and metastasis [40,41]. Studies using cytoplasmic hybrid (cybrid) technology to replace the endogenous mtDNA with another mtDNA mutant have shown that the mitochondrial genome damage might be associated with ROS production, apoptosis resistance, and increased metastasis [42,43].…”

Section: Discussionmentioning

confidence: 99%

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Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): a switch from aerobic to anaerobic metabolism

et al. 2012

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Nutrient deprivation and reactive oxygen species (ROS) play an important role in breast cancer mitochondrial adaptation. Adaptations to these conditions allow cells to survive in the stressful microenvironment of the tumor bed. This study is directed at defining the consequences of High Nitric Oxide (HNO) exposure to mitochondria in human breast cancer cells. The breast cancer cell line BT-20 (parent) was adapted to HNO as previously reported, resulting in the BT-20-HNO cell line. Both cell lines were analyzed by a variety of methods including MTT, LDH leakage assay, DNA sequencing, and Western blot analysis. The LDH assay and the gene chip data showed that BT-20-HNO was more prone to use the glycolytic pathway than the parent cell line. The BT-20-HNO cells were also more resistant to the apoptotic inducing agent salinomycin, which suggests that p53 may be mutated in these cells. Polymerase chain reaction (PCR) followed by DNA sequencing of the p53 gene showed that it was, in fact, mutated at the DNA-binding site (L194F). Western blot analysis showed that p53 was significantly upregulated in these cells. These results suggest that free radicals, such as nitric oxide (NO), pressure human breast tumor cells to acquire an aggressive phenotype and resistance to apoptosis. These data collectively provide a mechanism by which the dysregulation of ROS in the mitochondria of breast cancer cells can result in DNA damage.Keywords Breast cancer . Nitric oxide . p53 . Reactive oxygen species (ROS) . Glycolysis and apoptosis . Aerobic and anaerobic metabolisms

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): a switch from aerobic to anaerobic metabolism

et al. 2012

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“…During last two decades, association between mtDNA mutations and many human diseases including neurodegenerative diseases, metabolic diseases, and various types of cancer has been reported (Fliss et al, 2000;Penta et al, 2001;Wallace, 2005;Lu et al, 2009). Mitochondrion plays an essential role in different pathways in the cell such as energy production, reactive oxygen species (ROS) generation, and also in a fundamental biological process in which cells die in a controlled manner called apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial D-Loop Polymorphism and Microsatellite Instability in Prostate Cancer and Benign Hyperplasia Patients

Ashtiani

Heidari²,

Hasheminasab³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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In this study mitochondrial D-Loop variations in Iranian prostate cancer and benign prostatic hyperplasia (BPH) patients were investigated. Tumour samples and corresponding non-cancerous prostate tissue from 40 prostate cancer patients and 40 age-matched BPH patients were collected. The entire mtD-loop region (16024-576) was amplified using the PCR method and products were gel-purified and subjected to direct nucleotide sequencing. A total of 129 variations were found, the most frequent being 263AgG and 310TgC among both BPH and prostate cancer patients. Variation of 309 CgT was significantly more frequent in prostate cancer patients (P value<0.05). Four novel variations were observed on comparison with the MITOMAP database. Novel variations were np16154delT, np366GgA, np389GgA and 56insT. There was no correspondence between the different variations and the age of subjects. Considering that D-loop variations were frequent in both BPH and prostate cancer patients in our study, the fact that both groups had high average age can be a possible contributing factor. D-loop polymorphisms and microsatellite instability can influence cell physiology and result in a benign or malignant phenotype. Significantly higher frequency of 309 CgT variation in cancer patients is a notable finding and must be a focus of attention in future studies.

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“…This pathway is accomplished by a group of protein complexes and mitochondrial respiratory chains (MRC) which are controlled by both of nuclear and mitochondrial genomes (Higuchi, 2012). Several studies demonstrated that mtDNA mutation is common in cancer (Lu et al, 2009;Cook and Higuchi, 2011). Mitochondria play vital functions in ATP metabolism, free radical generation, and regulation of apoptosis, subsequently changes in mitochondrial DNA would affect cellular energy capacities, increase oxidative stress, trigger ROS-mediated damage to DNA, and alter the cellular response to apoptosis induction by anticancer agents (Carew et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

New Haplotypes of the ATP Synthase Subunit 6 Gene of Mitochondrial DNA are Associated with Acute Lymphoblastic Leukemia in Saudi Arabia

Yacoub¹,

Mahmoud²,

El-Baz³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Background: Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children and represents approximately 25% of cancer diagnoses among those younger than 15 years of age. Aim and Objectives: This study investigated substitutions in the ATP synthase subunit 6 gene of mitochondrial DNA (mtDNA) as a potential diagnostic biomarker for early detection and diagnosis of acute lymphoblastic leukemia. Based on mtDNA from 23 subjects diagnosed with acute lymphoblastic leukemia, approximately 465 bp of the ATP synthase subunit 6 gene were amplified and sequenced. Results: The sequencing revealed thirty-one mutations at 14 locations in ATP synthase subunit 6 of mtDNA in the ALL subjects. All were identified as single nucleotide polymorphisms (SNPs) with a homoplasmic pattern. The mutations were distributed between males and females. Novel haplotypes were identified in this investigation: haplotype (G) was recorded in 34% in diagnosed subjects; the second haplotype was (C) with frequency of 13% in ALL subjects. Neither of these were observed in control samples. Conclusions: These haplotypes were identified for the first time in acute lymphoblastic leukemia patients. Five mutations able to change amino acid synthesis for the ATP synthase subunit 6 were associated with acute lymphoblastic leukemia. This investigation could be used to provide an overview of incidence frequency of acute lyphoblastic leukemia (ALL) in Saudi patients based on molecular events.

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Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis

Cited by 240 publications

References 189 publications

Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): a switch from aerobic to anaerobic metabolism

Part III. Molecular changes induced by high nitric oxide adaptation in human breast cancer cell line BT-20 (BT-20-HNO): a switch from aerobic to anaerobic metabolism

Mitochondrial D-Loop Polymorphism and Microsatellite Instability in Prostate Cancer and Benign Hyperplasia Patients

New Haplotypes of the ATP Synthase Subunit 6 Gene of Mitochondrial DNA are Associated with Acute Lymphoblastic Leukemia in Saudi Arabia

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