Effekte der Adipositas auf oxidativen Stress und Stoffwechselinteraktionen zwischen Normal- und Tumorgewebe in der Pankreaskarzinogenese
Zusammenfassung der Projektergebnisse
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with high death rates shortly after diagnosis. Although several genes and signaling pathways are involved, mutation of K-RAS is the major driving force of this pathology and is detected in early premalignant lesions, termed pancreatic intraepithelial neoplasia (PanIN). Currently, there is no efficient means of therapy available. Although, there has been considerable amount of research that focuses on therapeutic approaches such as specific inhibition of these signaling pathways, unfortunately cancer-associated mortality rates show an increasing trend in the past decades questioning the validity of these current approaches. Epidemiological studies suggest diet-induced obesity is closely associated to cancer and increased BMI positively correlates with the mortality rates. Therefore, deregulation of energy metabolism may provide new avenues for possible therapeutic interventions. Here, we altered energy metabolism using a high-fat diet (HFD) in a tumor-prone mice with mutant k-ras activation (p48-KrasG12D mice). HFD increased tumor incidence significantly and this was associated with diminished mitochondrial oxidative phosphorylation due to decreased mitochondria number and impaired mitochondrial function, which forced tumor cells to switch towards glycolysis as the major bioenergetic pathway. The alteration in mitochondrial metabolism was corrected and tumor incidence was significantly abrogated upon 2-deoxyglucose (2-DG) treatment suggesting increased respiratory capacity through administration of a glucose analogue led to a switch from glycolysis to oxidative phosphorylation. Furthermore, inhibition of nuclear receptors PPARa and PPARg conferred total rescue against diet-induced tumorigenesis suggesting mitochondrial lipid metabolism and biogenesis a critical role during disease development in p48-KrasG12D mice. Moreover, reduced tumor incidence was associated with decreased inflammation and M2 macrophage polarization upon 2-DG treatment or PA deficiency in p48-KrasG12D mice. Indeed, the cause and consequence relationship between activation of inflammatory cells in the tumor microenvironment and derangements in mitochondrial energy metabolism may provide potential approaches for therapeutic interventions since PPAR agonists and antagonists are available and widely used for metabolic disorders.
Projektbezogene Publikationen (Auswahl)
- IkBb is an essential co-activator for LPS induced IL-1b transcription in vivo’. J. Ex. Med., Nov 22; 207(12]: 2621-30, 2010
Scheibel M, Klein B, Merkle H, Schulz MD, Fritsch R, Greten FR, Arkan MC, Schneider G and Schmid RM
- ‘Lymphotoxin ß receptor signaling promotes development of autoimmune pancreatitis’. Gastroenterology, Nov; 143(5]: 1361-74, 2012
Seleznik GM, Reding T, Romrig F, Saito Y, Mildner A, Segerer S, Sun LK, Regenass S, Lech M, Anders HJ, McHugh D, Kumagi T, Hiasa Y, Lackner C, Haybaeck J, Angst E, Perren A, Balmer ML, Slack E, MacPherson A, Manz MG, Weber A, Browning JL, Arkan MC, Rülicke T, Aguzzi A, Prinz M, Graf R, Heikenwalder M
(Siehe online unter https://doi.org/10.1053/j.gastro.2012.07.112) - ‘High-fat-diet-mediated dysbiosis promotes intestinal carcinogenesis independently of obesity’. Nature, Oct23; 514(7523): 508-512, 2014
Schulz MD, Atay C, Heringer J, Romrig FR, Schwitalla S, Aydin B, Ziegler PK, Varga J, Reindl W, Pommerenke C, Salinas-Riester G, Böck A, Alpert C, Blaut M, Polson SC, Brandl L, Kirchner T, Greten FR, Polson SW and Arkan MC
(Siehe online unter https://doi.org/10.1038/nature13398)
