Enhanced tumorigenicity by mitochondrial DNA mild mutations

Cruz-Bermúdez, Alberto; Vallejo, Carmen G.; Vicente-Blanco, Ramiro J.; Gallardo, M. Esther; Fernández-Moreno, Miguel Ángel; Quintanilla, Miguel; Garesse, Rafael

doi:10.18632/oncotarget.3698

Cited by 49 publications

(56 citation statements)

References 61 publications

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“…Since then, several other groups have reported similar findings although using different mtDNA mutations (6–12). Of interest, one group reported that mild mtDNA mutations were actually more potent at generating aggressive tumors compared to cells carrying mutations causing severe defect in OXPHOS (11). While in most studies the mechanism remained unclear, some have suggested that mtDNA mutations affecting OXPHOS act on invasion via a cross talk between cancer cell mitochondria and the extracellular matrix (12).…”

Section: Discussionmentioning

confidence: 99%

Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis

et al. 2017

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By causing mitochondrial DNA (mtDNA) mutations and oxidation of mitochondrial proteins, reactive oxygen species (ROS) leads to perturbations in mitochondrial proteostasis. Several studies have linked mtDNA mutations to metastasis of cancer cells but the nature of the mtDNA species involved remains unclear. Our data suggests that no common mtDNA mutation identifies metastatic cells; rather the metastatic potential of several ROS-generating mutations is largely determined by their mtDNA genomic landscapes, which can act either as an enhancer or repressor of metastasis. However, mtDNA landscapes of all metastatic cells are characterized by activation of the SIRT/FOXO/SOD2 axis of the mitochondrial unfolded protein response (UPR mt ). The UPR mt promotes a complex transcription program ultimately increasing mitochondrial integrity and fitness in response to oxidative proteotoxic stress. Using SOD2 as a surrogate marker of the UPR mt , we found that in primary breast cancers, SOD2 is significantly increased in metastatic lesions. We propose that the ability of selected mtDNA species to activate the UPR mt is a process that is exploited by cancer cells to maintain mitochondrial fitness and facilitate metastasis.

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Section: Discussionmentioning

confidence: 99%

Selected mitochondrial DNA landscapes activate the SIRT3 axis of the UPRmt to promote metastasis

et al. 2017

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“…It is well-known that cellular proliferation and survival, especially in tumor cells, is also related to Ras, whose activity is dependent on farnesylation [38]. Since 143B cells carry a Ras mutation [31,32] we reasoned that mevinolin-induced reduction of cellular viability could be also related to Ras defarnesylation. Interestingly, while impairment of Ras farnesylation by mevinolin was evident in 143B cells, the highest induction of apoptotic markers, including cleaved Caspase 3 and PARP (Poly (ADPribose) polymerase), was observed in mevinolin-treated MG63 cells (Figure 5c).…”

Section: Mevinolin Effects In Os Cells Are Related To Prelamin a Accumentioning

confidence: 98%

“…However, as compared to other OS cell lines, MG63 showed higher protein levels of lamin A (Figure 2a,b). The lowest lamin A/C levels were determined in HOS cells, and in the 143B Ras-mutated HOS-derived cell line [31,32] (Figure 2a,b). These data were also confirmed in other OS cell lines obtained in our laboratory (Supplementary Figure S1).…”

Section: Lamin A/c Expression Is Reduced In Osteosarcoma Cellsmentioning

confidence: 98%

Lamin A and Prelamin A Counteract Migration of Osteosarcoma Cells

Evangelisti

Paganelli

Giuntini

et al. 2020

Cells

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A type lamins are fundamental components of the nuclear lamina. Changes in lamin A expression correlate with malignant transformation in several cancers. However, the role of lamin A has not been explored in osteosarcoma (OS). Here, we wanted to investigate the role of lamin A in normal osteoblasts (OBs) and OS cells. Thus, we studied the expression of lamin A/C in OS cells compared to OBs and evaluated the effects of lamin A overexpression in OS cell lines. We show that, while lamin A expression increases during osteoblast differentiation, all examined OS cell lines express lower lamin A levels relative to differentiated OBs. The condition of low LMNA expression confers to OS cells a significant increase in migration potential, while overexpression of lamin A reduces migration ability of OS cells. Moreover, overexpression of unprocessable prelamin A also reduces cell migration. In agreement with the latter finding, OS cells which accumulate the highest prelamin A levels upon inhibition of lamin A maturation by statins, had significantly reduced migration ability. Importantly, OS cells subjected to statin treatment underwent apoptotic cell death in a RAS-independent, lamin A-dependent manner. Our results show that pro-apoptotic effects of statins and statin inhibitory effect on OS cell migration are comparable to those obtained by prelamin A accumulation and further suggest that modulation of lamin A expression and post-translational processing can be a tool to decrease migration potential in OS cells.

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“…Recent evidence indicates that, by acting at the ETC‐complexes level, certain polyphenols would be able to modulate the rate of mitochondrial superoxide production . The pathogenesis of both neurological disorders and cancer has been related to mitochondrial dysfunction . Mitochondrial dysfunction and consequent energy depletion are the major causes of oxidative stress resulting in alteration of ionic homeostasis and causing loss of cellular integrity.…”

Section: Introductionmentioning

confidence: 99%