Depletion of mitochondrial DNA up-regulates the expression of MDR1 gene via an increase in mRNA stability

Lee, Wan; Choi, Hyo I.; Kim, Mi Jin; Park, Seung Yoon

doi:10.3858/emm.2008.40.1.109

Cited by 53 publications

(34 citation statements)

References 33 publications

(43 reference statements)

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“…Several studies have presented evidence that mtDNA plays an important role in cellular sensitivity to cancer therapies (36). We and others have suggested that the mitochondrion could be the integrator of many signals that have a potential effect on tumor-related growth (13,19,36,(51)(52)(53)(54). Little is known however about the effect of long term exposure of an alkylating agent on mtDNA copy number and heteroplasmy in cancer cells, One possible explanation for the decreased mtDNA copy number is that expression of DNA polymerase-␥, the polymerase responsible for the replication and repair of mtDNA, is substantially reduced in TMZ-resistant cells, impairing replication of the mitochondrial genome.…”

Section: Discussionmentioning

confidence: 99%

Acquisition of Temozolomide Chemoresistance in Gliomas Leads to Remodeling of Mitochondrial Electron Transport Chain

Oliva

Nozell

Diers

et al. 2010

Journal of Biological Chemistry

164

199

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Temozolomide (TMZ) is an oral alkylating agent used for the treatment of high-grade gliomas. Acquired chemoresistance is a severe limitation to this therapy with more than 90% of recurrent gliomas showing no response to a second cycle of chemotherapy. Efforts to better understand the underlying mechanisms of acquired chemoresistance to TMZ and potential strategies to overcome chemoresistance are, therefore, critically needed. TMZ methylates nuclear DNA and induces cell death; however, the impact on mitochondria DNA (mtDNA) and mitochondrial bioenergetics is not known. Herein, we tested the hypothesis that TMZ-mediated alterations in mtDNA and respiratory function contribute to TMZ-dependent acquired chemoresistance. Using an in vitro model of TMZ-mediated acquired chemoresistance, we report 1) a decrease in mtDNA copy number and the presence of large heteroplasmic mtDNA deletions in TMZ-resistant glioma cells, 2) remodeling of the entire electron transport chain with significant decreases of complexes I and V and increases of complexes II/III and IV, and 3) pharmacologic and genetic manipulation of cytochrome c oxidase, which restores sensitivity to TMZ-dependent apoptosis in resistant glioma cells. Importantly, human primary and recurrent pairs of glioblastoma multiforme (GBM) biopsies as well as primary and TMZ-resistant GBM xenograft lines exhibit similar remodeling of the ETC. Overall these results suggest that TMZ-dependent acquired chemoresistance may be due to a mitochondrial adaptive response to TMZ genotoxic stress with a major contribution from cytochrome c oxidase. Thus, abrogation of this adaptive response may reverse chemoresistance and restore sensitivity to TMZ, providing a strategy for improved therapeutic outcomes in GBM patients.

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Section: Discussionmentioning

confidence: 99%

Acquisition of Temozolomide Chemoresistance in Gliomas Leads to Remodeling of Mitochondrial Electron Transport Chain

Oliva

Nozell

Diers

et al. 2010

Journal of Biological Chemistry

164

199

View full text Add to dashboard Cite

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“…49 Moreover, depletion of mtDNA in human hepatoma SK-Hep1 cells results in an adaptive increase in the expression of manganese superoxide dismutase (MnSOD) and other antioxidant enzymes that enabled the cancer cells to counteract oxidative stress or chemotherapeutic agents. 50 The depletion of mtDNA was also shown to increase the expression of the multidrug resistance 1 (MDR1) gene and hence to exhibit higher tolerance to anti-cancer agents in human colon cancer HCT-8 cells, 51 osteosarcoma 143B cells, 52 and hepatoma cells. 53 Chloramphenicol-induced mitochondrial stress in human hepatoma HepG2 cells and non-small cell lung cancer H1299 cells increases p21 expression and prevents mitomycin-induced apoptosis through a p21-dependent pathway.…”

Section: Mitochondrial Dysfunction Induced By Somatic Mtdna Alteratiomentioning

confidence: 99%

Role of mitochondrial dysfunction in cancer progression

Hsu¹,

Tseng

Lee³

2016

Exp Biol Med (Maywood)

222

161

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Deregulated cellular energetics was one of the cancer hallmarks. Several underlying mechanisms of deregulated cellular energetics are associated with mitochondrial dysfunction caused by mitochondrial DNA mutations, mitochondrial enzyme defects, or altered oncogenes/tumor suppressors. In this review, we summarize the current understanding about the role of mitochondrial dysfunction in cancer progression. Point mutations and copy number changes are the two most common mitochondrial DNA alterations in cancers, and mitochondrial dysfunction induced by chemical depletion of mitochondrial DNA or impairment of mitochondrial respiratory chain in cancer cells promotes cancer progression to a chemoresistance or invasive phenotype. Moreover, defects in mitochondrial enzymes, such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase, are associated with both familial and sporadic forms of cancer. Deregulated mitochondrial deacetylase sirtuin 3 might modulate cancer progression by regulating cellular metabolism and oxidative stress. These mitochondrial defects during oncogenesis and tumor progression activate cytosolic signaling pathways that ultimately alter nuclear gene expression, a process called retrograde signaling. Changes in the intracellular level of reactive oxygen species, Ca 2þ , or oncometabolites are important in the mitochondrial retrograde signaling for neoplastic transformation and cancer progression. In addition, altered oncogenes/ tumor suppressors including hypoxia-inducible factor 1 and tumor suppressor p53 regulate mitochondrial respiration and cellular metabolism by modulating the expression of their target genes. We thus suggest that mitochondrial dysfunction plays a critical role in cancer progression and that targeting mitochondrial alterations and mitochondrial retrograde signaling might be a promising strategy for the development of selective anticancer therapy.

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“…For Western blot analysis, an equal amount of protein was subjected to electrophoresis on SDS-polyacrylamide gel and transferred to a nitrocellulose membrane (Schleicher & Schuell, Keene, NH) by electroblotting. Blots were probed with the desired antibodies for 1 h, incubated with the diluted enzyme-linked secondary antibodies, and visualized by enhanced chemiluminescence (ECL) Western blotting detection reagents (SuperSignal, Thermo scientific, Rockford, IL) according to the recommended procedure (31).…”

Section: Methodsmentioning

confidence: 99%

Apoptosis induction by glycoprotein isolated from Laminaria japonica is associated with down-regulation of telomerase activity and prostaglandin E2 synthesis in AGS human gastric cancer cells

Han

Kim²,

Moon³

et al. 2011

Int J Oncol

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Abstract. Glycoprotein isolated from Laminaria japonica (LJGP) is known to exhibit significant cytotoxic activity against human cancer cells; however, the mechanisms of its cytoxicity are poorly understood. In this study, we investigated further possible mechanisms by which LJGP exerts its anti-cancer action in cultured human gastric carcinoma AGS cells. LJGP treatment of AGS cells resulted in inhibition of growth and induction of apoptosis in a time-and concentrationdependent manner, as determined by MTT assay, fluorescence microscopy, and flow cytometry analysis. The increase in apoptosis was associated with up-regulation of pro-apoptotic Bax expression, down-regulation of anti-apoptotic Bcl-2 and IAP family members, and activation of caspase-3 and -9. LJGP treatment markedly down-regulated the activity of telomerase and expression of human telomerase reverse transcriptase, a main determinant of telomerase enzymatic activity, with inhibition of Sp1 and c-Myc expression in a concentration-dependent manner. Furthermore, LJGP treatment also caused a progressive decrease in the expression levels of cyclooxygenase (COX)-2 without significant changes in the levels of COX-1, which was correlated with a decrease in prostaglandin E 2 synthesis. These results provide important new insights into the possible molecular mechanisms of the anti-cancer activity of LJGP.

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Depletion of mitochondrial DNA up-regulates the expression of MDR1 gene via an increase in mRNA stability

Cited by 53 publications

References 33 publications

Acquisition of Temozolomide Chemoresistance in Gliomas Leads to Remodeling of Mitochondrial Electron Transport Chain

Acquisition of Temozolomide Chemoresistance in Gliomas Leads to Remodeling of Mitochondrial Electron Transport Chain

Role of mitochondrial dysfunction in cancer progression

Apoptosis induction by glycoprotein isolated from Laminaria japonica is associated with down-regulation of telomerase activity and prostaglandin E2 synthesis in AGS human gastric cancer cells

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