Oncogene-induced reactive oxygen species fuel hyperproliferation and DNA damage response activation

Öğrünç, Müge; Micco, Raffaella Di; Liontos, Michalis; Bombardelli, Lorenzo; Mione, Marina; Fumagalli, Marzia; Gorgoulis, Vassilis G.; Fagagna, Fabrizio d’Adda di

doi:10.1038/cdd.2014.16

Cited by 275 publications

(207 citation statements)

References 63 publications

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“…The most frequent are endogenous causes, which arise mainly from increased ROS (reactive oxygen species) production, due to metabolic stress. Activated oncogenes are again responsible for ROS generation (25)(26)(27). in vivo 31: 527-542 (2017) Therefore, although we are aware that the inactivation of a ts gene initiates colorectal tumorigenesis, the origin of its inactivation is unfamiliar.…”

Section: Questions Associated With the Current Model Of Colorectal Tumentioning

confidence: 99%

“…They seem to be crucial for K-ras-induced cellular transformation (81) and indispensable for the tumorigenic effect of Ras mutated cells: oncogenic Ras-expressing cells depend on ROS for their proliferation. Similarly the DDR-activating factors of ROS are dependent on the ongoing replication, acting only on a proliferating cell (27) (Figure 2). …”

Section: Why Is K-ras Mutation a Potential Alternative Initiating Evementioning

confidence: 99%

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K-ras Mutations as the Earliest Driving Force in a Subset of Colorectal Carcinomas

Margetis

Kouloukoussa

Pavlou

et al. 2017

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Section: Questions Associated With the Current Model Of Colorectal Tumentioning

confidence: 99%

Section: Why Is K-ras Mutation a Potential Alternative Initiating Evementioning

confidence: 99%

K-ras Mutations as the Earliest Driving Force in a Subset of Colorectal Carcinomas

Margetis

Kouloukoussa

Pavlou

et al. 2017

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“…To determine cell proliferation, the same cells were grown in parallel on coverslips and subjected to a 3-hour pulse of BrdU (Sigma-Aldrich) after doxycycline treatment. Cells were then fixed and stained for BrdU as in Ogrunc et al, 2014. 62 BrdU positive cells were counted with CellProfiler software (cellprofiler.org).…”

Section: Generation Of Stable and Inducible Be(2)-c Cell Line Expressmentioning

confidence: 99%

“…Cells were then fixed and stained for BrdU as in Ogrunc et al, 2014. 62 BrdU positive cells were counted with CellProfiler software (cellprofiler.org). 63 At least 150 cells were analyzed for each sample.…”

Section: Generation Of Stable and Inducible Be(2)-c Cell Line Expressmentioning

confidence: 99%

Identification of linc-NeD125, a novel long non coding RNA that hosts miR-125b-1 and negatively controls proliferation of human neuroblastoma cells

et al. 2015

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“…due to activation of Rac1-NOX4 signaling. 13 For example, Rac1 in Kras G12D -expressing PanIN1B/PanIN2 is increasingly active when the tumor protein p53-induced nuclear protein 1 (TP53INP1) is knocked out or decreasingly expressed. 14 Other mechanisms by which increases in intracellular ROS can be achieved include enhanced growth factor signaling, 15,16 KRas G12D -induced induction of autophagy-specific genes 5 and 7 (ATG5, ATG7), 17 repression of SESN3, which controls the regeneration of peroxiredoxins, 18 or expression of micro RNAs such as miR-155.…”

mentioning

confidence: 99%

KRas, ROS and the initiation of pancreatic cancer

Störz

2016

Small GTPases

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Oncogenic mutations of KRAS are the most frequent driver mutations in pancreatic cancer. Expression of an oncogenic allele of KRAS leads to metabolic changes and altered cellular signaling that both can increase the production of intracellular reactive oxygen species (ROS). Increases in ROS have been shown to drive the formation and progression of pancreatic precancerous lesions by upregulating survival and growth factor signaling. A key issue for precancerous and cancer cells is to keep ROS at levels where they are beneficial for tumor development and progression, but below the threshold that leads to induction of senescence or cell death. In KRas-driven neoplasia aberrantly increased ROS levels are therefore balanced by an upregulation of antioxidant genes. KEYWORDSKRas; mitochondria; oxidative stress; pancreatic cancer; PanIN; ROS Epidemiological and animal studies suggest that supplementation of dietary antioxidants decreases cancer risk, which implies that increased ROS may play a role in carcinogenesis. 1 Approximately 95% of all pancreatic ductal adenocarcinoma (PDA) show acquisition of activating KRAS mutations, 2 which, due to oncogene-mediated alterations in the cell's metabolism, goes along with increased cellular oxidative stress levels. [3][4][5][6] In mouse models for development of PDA, KRas-caused formation of ROS already is induced in acinar cells and gradually increased during ADM and PanIN formation and progression 5 (Fig. 1).In pancreatic cancer, oncogenic KRas induces the generation of ROS through multiple mechanisms. Typical metabolic changes initiated by tumor cells are, for example, an increase in aerobic glycolysis (Warburg effect) to support growth under hypoxic conditions 7 or altered mitochondrial metabolic activity. 5,6,[8][9][10] Oncogenic KRas can modulate mitochondrial metabolism and ROS generation by regulating hypoxia-inducible factors (HIFs) HIF-1a and HIF-2a, 8 or through regulation of the transferrin receptor (TfR1), which is highly expressed in pancreatic cancers. 11 In addition, KRas can induce suppression of respiratory chain complex I and III to cause mitochondrial dysfunction. 6,12 Decreased mitochondrial efficiency then results in an increased production of ROS. 5 A possible cause is the ROS-mediated occurrence of 4-hydroxy-2-nonenal (4HNE) and 4HNE-adduct formation with macromolecules, which can lead to inhibition of mitochondrial proteins or damage of mtDNA. 5 KRas-induced increases in intracellular ROS levels can also occur via altered NADPH oxidase activities, 1 i.e. due to activation of Rac1-NOX4 signaling. 13 For example, Rac1 in Kras G12D -expressing PanIN1B/PanIN2 is increasingly active when the tumor protein p53-induced nuclear protein 1 (TP53INP1) is knocked out or decreasingly expressed. 14 Other mechanisms by which increases in intracellular ROS can be achieved include enhanced growth factor signaling, 15,16 KRas G12D -induced induction of autophagy-specific genes 5 and 7 (ATG5, ATG7), 17 repression of SESN3, which controls the regeneration of peroxi...

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Oncogene-induced reactive oxygen species fuel hyperproliferation and DNA damage response activation

Cited by 275 publications

References 63 publications

K-ras Mutations as the Earliest Driving Force in a Subset of Colorectal Carcinomas

K-ras Mutations as the Earliest Driving Force in a Subset of Colorectal Carcinomas

Identification of linc-NeD125, a novel long non coding RNA that hosts miR-125b-1 and negatively controls proliferation of human neuroblastoma cells

KRas, ROS and the initiation of pancreatic cancer

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