The causes of cancer revisited: “Mitochondrial malignancy” and ROS-induced oncogenic transformation – Why mitochondria are targets for cancer therapy

Ralph, Stephen John; Rodrı́guez-Enrı́quez, Sara; Neužil, Jiřı́; Saavedra, Emma; Moreno‐Sánchez, Rafael

doi:10.1016/j.mam.2010.02.008

Cited by 308 publications

(286 citation statements)

References 199 publications

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“…11,20,21 In line with these studies, we observed that K-Ras V12 transforms normal fibroblasts in association with ROS generation, causing acquisition of anchorage-independent colony-forming ability and increased tumor-forming capacity. In this study, we found that K-Ras V12 -induced ROS generation occurs through NOX1.…”

Section: Discussionsupporting

confidence: 73%

“…18 In lung epithelial cells, oncogenic K-Ras expression promoted ROS generation through cyclooxygenase (COX)-2, causing DNA damages and malignant transformation. 19 Although mitochondrial ROS production was suggested to be important for Ras-driven malignant transformation, 20 Ras increased ROS through NADPH oxidase 1 (NOX1) that is a plasma membrane-bound enzyme, finally causing malignant transformation. 21 However, the precise molecular mechanisms underlying K-Ras-induced ROS generation remain largely unknown.…”

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confidence: 99%

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Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

et al. 2014

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Reactive oxygen species (ROS) are well known to be involved in oncogene-mediated cellular transformation. However, the regulatory mechanisms underlying ROS generation in oncogene-transformed cells are unclear. In the present study, we found that oncogenic K-Ras induces ROS generation through activation of NADPH oxidase 1 (NOX1), which is a critical regulator for the K-Ras-induced cellular transformation. NOX1 was activated by K-Ras-dependent translocation of p47 phox , a subunit of NOX1 to plasma membrane. Of note, PKCd, when it was activated by PDPK1, directly bound to the SH3-N domain of p47 phox and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47 phox C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation. Notably, oncogenic K-Ras activated all MAPKs (JNK, ERK and p38); however, only p38 was involved in p47 phox -NOX1-dependent ROS generation and consequent transformation. Importantly, K-Ras-induced activation of p38 led to an activation of PDPK1, which then signals through PKCd, p47 phox and NOX1. In agreement with the mechanism, inhibition of p38, PDPK1, PKCd, p47 phox or NOX1 effectively blocked K-Ras-induced ROS generation, anchorage-independent colony formation and tumor formation. Taken together, our findings demonstrated that oncogenic K-Ras activates the signaling cascade p38/ PDPK1/PKCd/p47 phox /NOX1 for ROS generation and consequent malignant cellular transformation.

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Section: Discussionsupporting

confidence: 73%

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confidence: 99%

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

et al. 2014

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“…It has been proposed that cancer outcomes are the result of variations in the microenvironment, which is a driving force in the clonal selection of cells with genetic and metabolic alterations resulting in angiogenesis, invasion, and metastasis [2,3]. Reactive oxygen species (ROS) and reactive nitrogen species (RNS), such as hydrogen peroxide (H 2 O 2 ) and nitric oxide (NO), when present in high concentration and prolonged stimulus have been implicated in the pathophysiology of cancer as agents that alter cell homeostasis [4,5].…”

Section: Introductionmentioning

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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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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“…The genetic variation and the effects of tumour environmental cues such as oxygen variability might contribute to the tumour heterogeneity and development. The producing and neutralizing of ROS are pivotal in tumour development because many factors, lipids and nucleic acids are downstream targets of ROS 15, 16, 17. Several studies revealed that unregulated and augmented ROS could initiate redox‐linked signalling responses and irreversible injuries in RCC 18, 19.…”

Section: Discussionmentioning

confidence: 99%

A novel functional polymorphism of GSTM3 reduces clear cell renal cell carcinoma risk through enhancing its expression by interfering miR‐556 binding

Wang

Yang

Chen

et al. 2018

J Cellular Molecular Medi

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Dysregulation of glutathione‐S‐transferase M3 (GSTM3) has been related to clear cell renal cell carcinoma (ccRCC) in our former study. GSTM3 plays a pivotal role of detoxification and clearance of reactive oxygen species (ROS) in tumour tissues. This study aimed to examine: (1) the associations between GSTM3 single nucleotide polymorphisms (SNPs) and risk of ccRCC, and (2) the potential molecular mechanism accounting for its effects. 5 SNPs in 3′UTR of GSTM3 were initially genotyped in 329 cases and 420 healthy controls. A SNP‐rs1055259 was found to be significantly associated with the susceptibility of ccRCC (OR = 0.59, 95% CI = 0.41‐0.92; P = .019). The minor allele of rs1055259 (G allele) was associated with RCC risk. This SNP was predicted to affect microRNA (miR)‐556 binding to 3′UTR of GSTM3 mRNA. To determine the functional impact, plasmid constructs carrying different alleles of rs1055259 were created. Compared to rs1055259 A‐allele constructs, cells transfected with rs1055259 G‐allele construct had higher transcriptional activity and were less responsive to miR‐556 changes and gene expression. Elevated GSTM3 expression in G‐allele cells was associated with ROS activity and ccRCC development. Taken together, this study indicated that a functional polymorphism of GSTM3 ‐rs1055259 reduced susceptibility of RCC in the Chinese population. It influenced GSTM3 protein synthesis by interfering miR‐556 binding, subsequently suppressed ROS activity and ccRCC progression.

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The causes of cancer revisited: “Mitochondrial malignancy” and ROS-induced oncogenic transformation – Why mitochondria are targets for cancer therapy

Cited by 308 publications

References 199 publications

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation

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

A novel functional polymorphism of GSTM3 reduces clear cell renal cell carcinoma risk through enhancing its expression by interfering miR‐556 binding

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