Pancreatic oncogenic signaling cascades converge at Protein Kinase D1

Liou, Geou-Yarh; Leitges, Michael; Störz, Peter

doi:10.1080/15384101.2015.1032646

Cell Cycle

2015

DOI: 10.1080/15384101.2015.1032646

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Pancreatic oncogenic signaling cascades converge at Protein Kinase D1

Geou-Yarh Liou

Michael Leitges

Peter Störz

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2016

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“…[30][31][32] An emerging key-role of PKD1 for the initiation of pancreatic cancer is indicated by its additional involvement in the activation of Notch signaling downstream of mutant and wildtype KRas. 22,33 Notch and NF-kB signaling pathways can co-operate to mediate formation of pre-neoplastic lesions. 34 Thus PKD1 brings together 2 important pathways that drive the formation of precancerous lesions.…”

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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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KRas, ROS and the initiation of pancreatic cancer

Störz

2016

Small GTPases

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Pancreatic oncogenic signaling cascades converge at Protein Kinase D1

Cited by 1 publication

References 7 publications

KRas, ROS and the initiation of pancreatic cancer

KRas, ROS and the initiation of pancreatic cancer

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