AMPK and Nrf2 drive redox-metabolic reprogramming of cancer-associated adipose tissue in breast cancer
2021
Аутори:
Kalezić, AnđelikaUdički, Mirjana
Srdić Galić, Biljana
Korać, Aleksandra
Janković, Aleksandra
Korać, Bato
Тип документа:
Конференцијски прилог (Објављена верзија)
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© 2021 Published by Elsevier Inc.
Метаподаци
Приказ свих података о документуАпстракт:
Breast cancer behaves as a complex pseudo-organ where the adaptive behavior of cancer cells is deeply context-dependent, reflecting various local and systemic influences. Recently, cancer-associated adipocytes emerged as critical players in cancer progression, adapting to metabolic demands of proliferating cancer cells and responding through the supply of diverse energy substrates. To decipher underlying mechanisms that enable such plastic response, we cross-examined biopsies of cancer-associated adipose tissue from normal-weight and overweight women with invasive ductal carcinoma compared to mammary adipose tissue of weight-matched women with benign fibroadenoma. To that end, we analyzed mitochondrial copy number and master regulators of energy and redox homeostasis (AMP-activated protein kinase – AMPK and nuclear factor erythroid 2-related factor 2 – Nrf2), followed by key enzymes in their downstream pathways such as glycolysis, pentose phosphate pathway, fatty acid oxidation, and antioxidant defense. Compared to mammary adipose tissue, cancer-associated adipose tissue showed concomitantly higher AMPK and Nrf2 protein expression followed by overexpression of hexokinase 2, glucose-6-phosphate dehydrogenase, peroxisomal acyl-coenzyme A oxidase 1, first-line antioxidant defense enzymes (CuZn- and Mn- superoxide dismutase and catalase), as well as higher mitochondrial copy number. In contrast, in cancer-associated adipose tissue of obese women, a sole increase in AMPK protein expression without Nrf2 was followed by increased protein expression of analyzed metabolic enzymes but not antioxidant defense enzymes or mitochondrial copy number. The results indicate that simultaneous activation of AMPK and Nrf2 signaling promotes a specific metabolic phenotype of cancer-associated adipose tissue, resembling the Warburg effect with high mitochondrial content and increased redox homeostasis threshold. Moreover, context-dependent disruption of the AMPK–Nrf2 axis could prevent the establishment of such phenotype in obesity
У:
- Free Radical Research Europe (SFRR-E): Annual Meeting Abstracts: “Redox biology in the 21st century: a new scientific discipline”; 2021 Jun 15-18; Belgrade, Serbia. Elsevier; 2021. p. S76-7. (Free Radical Biology and Medicine; Vol. 177; Suppl. 1).