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Nuclear factor E2-related factor-2 has a differential impact on MCT1 and MCT4 lactate carrier expression in colonic epithelial cells: a condition favoring metabolic symbiosis between colorectal cancer and stromal cells

Oncogene volume 37, pages 39–51 (2018)Cite this article

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Abstract

Malignant tumors, such as colorectal cancer (CRC), are heterogeneous diseases characterized by distinct metabolic phenotypes. These include Warburg- and reverse Warburg phenotypes depending on differential distribution of the lactate carrier proteins monocarboxylate transporter-4 and -1 (MCT4 and MCT1). Here, we elucidated the role of the antioxidant transcription factor nuclear factor E2-related factor-2 (Nrf2) as the key regulator of cellular adaptation to inflammatory/environmental stress in shaping the metabolism toward a reverse Warburg phenotype in malignant and premalignant colonic epithelial cells. Immunohistochemistry of human CRC tissues revealed reciprocal expression of MCT1 and MCT4 in carcinoma and stroma cells, respectively, accompanied by strong epithelial Nrf2 activation. In colorectal tissue from inflammatory bowel disease patients, MCT1 and Nrf2 were coexpressed as well, relating to CD68+inflammatory infiltrates. Indirect coculture of human NCM460 colonocytes with M1- but not M2 macrophages induces MCT1 as well as G6PD, LDHB and TALDO expression, whereas MCT4 expression was decreased. Nrf2 knockdown or reactive oxygen species (ROS) scavenging blocked these coculture effects in NCM460 cells. Likewise, Nrf2 knockdown inhibited similar effects of tBHQ-mediated Nrf2 activation on NCM460 and HCT15 CRC cells. M1 coculture or Nrf2 activation/overexpression greatly altered the lactate uptake but not glucose uptake and mitochondrial activities in these cells, reflecting the reverse Warburg phenotype. Depending on MCT1-mediated lactate uptake, Nrf2 conferred protection from TRAIL-induced apoptosis in NCM460 and HCT15 cells. Moreover, metabolism-dependent clonal growth of HCT15 cells was induced by Nrf2-dependent activation of MCT1-driven lactate exchange. These findings indicate that Nrf2 has an impact on the metabolism already in premalignant colonic epithelial cells exposed to inflammatory M1 macrophages, an effect accompanied by growth and survival alterations. Favoring the reverse Warburg effect, these Nrf2-dependent alterations add to malignant transformation of the colonic epithelium.

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Acknowledgements

We thank Maike Witt-Ramdohr and Iris Kosmol (both from the Institute of Experimental Cancer Research), and Sandra Krüger and Deniza Hajzeri (both from the Institute of Pathology) for excellent technical assistance. We also thank Dr Jens Dischinger for supporting with radioactivity experiments. Financial support by the Wilhelm-Sander-Stiftung (2015.011.01 to HS), the German-Cancer-Aid (111555 to KD) and the Cluster of Excellence ‘Inflammation at Interfaces’ (to HS, AA and SS) is greatly acknowledged.

Author contributions

KD, LD, OH, DP and NA conducted the experiments. CR and AA contributed to histochemistry experiments and data analysis. SS and HS designed the study and wrote the manuscript. All authors read and approved the contents of the manuscript and its publication.

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Authors and Affiliations

  1. Department of Internal Medicine I—Laboratory of Molecular Gastroenterology, UKSH Campus Kiel, Kiel, Germany

    K Diehl, A Arlt & H Schäfer

  2. Institute for Experimental Cancer Research—Christian-Albrechts-University, UKSH Campus Kiel, Kiel, Germany

    L-A Dinges, O Helm, N Ammar, D Plundrich, S Sebens & H Schäfer

  3. Institute of Pathology—Christian-Albrechts-University, UKSH Campus Kiel, Kiel, Germany

    C Röcken

  4. Biomaterial Bank of the Comprehensive Cancer Center Kiel, UKSH Campus Kiel, Kiel, Germany

    C Röcken & S Sebens

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  1. K Diehl
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This work is part of a doctoral thesis (KD and LAD).

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Diehl, K., Dinges, LA., Helm, O. et al. Nuclear factor E2-related factor-2 has a differential impact on MCT1 and MCT4 lactate carrier expression in colonic epithelial cells: a condition favoring metabolic symbiosis between colorectal cancer and stromal cells. Oncogene 37, 39–51 (2018). https://doi.org/10.1038/onc.2017.299

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