Progressive tumor features accompany epithelial–mesenchymal transition induced in mitochondrial DNA–depleted cells

Naito, Akira; Cook, Cody C.; Mizumachi, Takatsugu; Wang, Mian; Xie, Cheng-Hui; Evans, Teresa; Kelly, Thomas J.; Higuchi, Masahiro

doi:10.1111/j.1349-7006.2008.00879.x

Cited by 69 publications

(72 citation statements)

References 29 publications

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“…Transfer of mutated mtDNA from highly metastatic cell lines is sufficient to initiate a metastatic phenotype in non-metastatic cell lines by promoting mitochondrial ROS production (Ishikawa et al, 2008). Moreover, mtDNA depletion in MCF-7 cells induces an EMT programme (Naito et al, 2008). Our results show that PNC1, by regulating the mitochondrial ROS production, has the potential to regulate initiation of an ROS-dependent EMT programme in tumour cells.…”

Section: Pnc1 Regulates Mitochondrial Function and Emtmentioning

confidence: 72%

Mitochondrial pyrimidine nucleotide carrier (PNC1) regulates mitochondrial biogenesis and the invasive phenotype of cancer cells

et al. 2010

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The insulin-like growth factor (IGF-I) signalling pathway is essential for metabolism, cell growth and survival. It induces expression of the mitochondrial pyrimidine nucleotide carrier 1 (PNC1) in transformed cells, but the consequences of this for cell phenotype are unknown. Here we show that PNC1 is necessary to maintain mitochondrial function by controlling mitochondrial DNA replication and the ratio of transcription of mitochondrial genes relative to nuclear genes. PNC1 suppression causes reduced oxidative phosphorylation and leakage of reactive oxygen species (ROS), which activates the AMPK-PGC1a signalling pathway and promotes mitochondrial biogenesis. Overexpression of PNC1 suppresses mitochondrial biogenesis. Suppression of PNC1 causes a profound ROS-dependent epithelialmesenchymal transition (EMT), whereas overexpression of PNC1 suppresses both basal EMT and induction of EMT by TGF-b. Overall, our findings indicate that PNC1 is essential for mitochondria maintenance and suggest that its induction by IGF-I facilitates cell growth whereas protecting cells from an ROS-promoted differentiation programme that arises from mitochondrial dysfunction.

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Section: Pnc1 Regulates Mitochondrial Function and Emtmentioning

confidence: 72%

Mitochondrial pyrimidine nucleotide carrier (PNC1) regulates mitochondrial biogenesis and the invasive phenotype of cancer cells

et al. 2010

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“…To approach this question, we have silenced hnRNP A2/B1 in a panel of lung cancer cell lines that present a different EMT phenotype: mesenchymal H1703, intermediate A549, and epithelial H358 (30). EMT differentiation has been reported to affect migration and proliferation (28,29), and EMT induction has been observed as part of a response to mitochondrial stress (27).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, it has been reported that depletion of mitochondrial DNA in cancer cells promotes epithelial-mesenchymal transition (EMT; ref. 27). Moreover, it has also been proposed that changes in morphology, invasion, and metastasis potential could be the result of EMT (28,29).…”

Section: Introductionmentioning

confidence: 99%

hnRNP A2/B1 Modulates Epithelial-Mesenchymal Transition in Lung Cancer Cell Lines

et al. 2010

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Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1) has been reported to be overexpressed in lung cancer and in other cancers such as breast, pancreas, and liver. However, a mechanism linking hnRNP A2/ B1 overexpression and progression to cancer has not yet been definitively established. To elucidate this mechanism, we have silenced hnRNPA2/B1 mRNA in non-small-cell lung cancer cell lines A549, H1703, and H358. These cell lines present different levels of expression of epithelial-to-mesenchymal transition (EMT) markers such as E-cadherin, fibronectin, and vimentin. Microarray expression analysis was performed to evaluate the effect of silencing hnRNP A2/B1 in A549 cells. We identified a list of target genes, affected by silencing of hnRNP A2/B1, that are involved in regulation of migration, proliferation, survival, and apoptosis. Silencing hnRNP A2/ B1 induced formation of cell clusters and increased proliferation. In the anchorage-independent assay, silencing hnRNP A2/B1 increased colony formation by 794% in A549 and 174% in H1703 compared with a 25% increase in proliferation, in both cell lines, in a two-dimensional proliferation assay. Silencing hnRNP A2/B1 decreased migration in intermediate cell line A549 and mesenchymal cell line H1703; however, no changes in proliferation were observed in epithelial cell line H358. Silencing hnRNP A2/B1 in A549 and H1703 cells correlated with an increase of E-cadherin expression and downregulation of the E-cadherin inhibitors Twist1 and Snai1. These data suggest that expression of hnRNP A2/B1 may play a role in EMT, in nonepithelial lung cancer cell lines A549 and H1703, through the regulation of E-cadherin expression.

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“…22 The knock-out of the mtDNA (mtDNA-KO) from LNCaP and MCF-7 was demonstrated in the creation of the LNr0-8 and MCFr0 cell lines, respectively. 9,10 To confirm that experimental observations that follow the loss of the mitochondrial genome content are not of consequence to an incidental mutation to the nuclear genome induced by ethidium bromide treatment, the mitochondrial genome was reconstituted to the mtDNA-KO cell lines (LNr0-8 and MCFr0) in the creation of the mtDNA-knock in (mtDNA-KI) cells lines, denoted as LNCyb and MCFCyb.…”

Section: Resultsmentioning

confidence: 99%

“…We showed following observations to demonstrate the mechanisms involved in the induction of advanced phenotype of PCa by the reduction of mitochondrial genome content. Reduction of mtDNA content shifted (1) androgen-dependent PCa cells to an androgenindependent phenotype in vitro and in vivo 9 and induced (2) epithelial-to-mesenchymal transition changes that may lead to PCa progression, 10 (3) hypermethylation of CpG islands of the putative tumor suppressor genes 11 and (4) abnormal activation of NF-kB, 12 AP-1, 12 AKT, 13 ERK 10 and JNK 10 that may lead to aggressive phenotype in PCa progression.…”

Section: Subject Category: Cancermentioning

confidence: 99%

1330 Consumption of Oxygen: A Mitochondrial-Generated Progression Signal of Advanced Cancer

Kim

Cook

Gotoh³

et al. 2013

Journal of Urology

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Changes in mitochondrial genome such as mutation, deletion and depletion are common in cancer and can determine advanced phenotype of cancer; however, detailed mechanisms have not been elucidated. We observed that loss of mitochondrial genome reversibly induced overexpression and activation of proto-oncogenic Ras, especially K-Ras 4A, responsible for the activation of AKT and ERK leading to advanced phenotype of prostate and breast cancer. Ras activation was induced by the overexpression of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), the rate-limiting enzyme of the mevalonate pathway. Hypoxia is known to induce proteasomal degradation of HMGR. Well differentiated prostate and breast cancer cells with high mitochondrial DNA content consumed a large amount of oxygen and induced hypoxia. Loss of mitochondrial genome reduced oxygen consumption and increased in oxygen concentration in the cells. The hypoxic-to-normoxic shift led to the overexpression of HMGR through inhibiting proteasomal degradation. Therefore, reduction of mitochondrial genome content induced overexpression of HMGR through hypoxic to normoxic shift and subsequently the endogenous induction of the mevalonate pathway activated Ras that mediates advanced phenotype. Reduction of mitochondrial genome content was associated with the aggressive phenotype of prostate cancer in vitro cell line model and tissue specimens in vivo. Our results elucidate a coherent mechanism that directly links the mitochondrial genome with the advanced progression of the disease.

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Progressive tumor features accompany epithelial–mesenchymal transition induced in mitochondrial DNA–depleted cells

Cited by 69 publications

References 29 publications

Mitochondrial pyrimidine nucleotide carrier (PNC1) regulates mitochondrial biogenesis and the invasive phenotype of cancer cells

Mitochondrial pyrimidine nucleotide carrier (PNC1) regulates mitochondrial biogenesis and the invasive phenotype of cancer cells

hnRNP A2/B1 Modulates Epithelial-Mesenchymal Transition in Lung Cancer Cell Lines

1330 Consumption of Oxygen: A Mitochondrial-Generated Progression Signal of Advanced Cancer

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