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The RB–IL-6 axis controls self-renewal and endocrine therapy resistance by fine-tuning mitochondrial activity

Oncogene volume 36, pages 5145–5157 (2017)Cite this article

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Abstract

Retinoblastoma (RB) protein inactivation during tumor progression is often associated with acquisition of immature phenotypes and resistance to therapy. Determination of an RB inactivation signature in a context of gaining undifferentiated phenotype in a p53-null sarcoma system revealed a critical role for interleukin (IL)-6. Using a Gene Set Enrichment Analysis (GSEA), we discovered that poorly differentiated breast cancers are enriched for this RB inactivation signature. Accelerated IL-6 secretion following RB inactivation in an RB-intact luminal-type breast cancer cell line MCF-7 promoted a positive feed forward loop between IL-6 and STAT3 driving tumor growth and endocrine therapy resistance. In addition, some of RB-intact basal-like type breast cancer cell lines exhibited a similar phenotype following RB depletion. The mechanism whereby RB inactivation increases IL-6 production in MCF-7 cells appeared to involve fatty acid oxidation (FAO)-dependent mitochondrial metabolism and c-Jun NH(2)-terminal kinase (JNK). In addition, IL-6, via STAT3-mediated feedback to mitochondria, autonomously adjusts mitochondrial superoxide to levels suitable to maintain stem cell-like activity. The gene expression profile of luminal-type breast cancer patients with low RB expression revealed high enrichment of genes involved in mitochondrial respiration and downstream targets of IL-6. These findings unveiled an unexpected strategy whereby RB suppresses malignant features of cancer cells through metabolic reprogramming and cell-autonomous inflammation.

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Acknowledgements

We thank Drs T Kitamura, N Mukaida, K Yoshioka and Chugai Pharmaceuticals Co. Ltd. for providing materials, Drs T Baba, K Hinohara, A Hirao, T Hoshii, A Ishimura, K Matsumoto, K Sakai, S Sasaki, T Sato, T Shimamura, T Suzuki and Y Tadokoro for technical instruction, Dr A Ooi for pathological diagnosis, Drs I Ajioka and R Jenkins for critical reading of this manuscript, and Dr C Prives for advice. This work was supported by Funding Program for Next Generation World-Leading Researchers to CT, Grant-in-Aid for Scientific Research to CT, S Kitajima and NS, and Hokuriku Bank Research Grant for Young Scientists to S Kitajima.

Author contributions

CT and SK designed research; SK, AY, SK, FL, SS, NN, YN, NS, HM, YW, TT, NO, FM, HS, TN, YS, KT, NG, MS, OH and TT performed research. CT, SK and AY analyzed data. MME and DAB provided materials and opinion. CT and SK wrote manuscript.

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Authors and Affiliations

  1. Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan

    S Kitajima, A Yoshida, S Kohno, F Li, N Nagatani, Y Nishimoto, N Sasaki, H Muranaka, Y Wan, M Suzuki & C Takahashi

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    S Kitajima, T C Thai & D A Barbie

  3. Department of Cellular Transplantation Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan

    A Yoshida

  4. Department of Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan

    S Suzuki & T Tanaka

  5. Department of Bioinformatic Engineering, Graduate School of Information Science and Technology, Osaka University, Suita, Osaka, Japan

    N Okahashi, F Matsuda & H Shimizu

  6. Division of Functional Genomics, Advanced Science Research Center, Kanazawa University, Kanazawa, Ishikawa, Japan

    T Nishiuchi

  7. Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, Chiba, Japan

    Y Suzuki

  8. Division of Molecular Therapy, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan

    K Tominaga

  9. Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan

    N Gotoh

  10. Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA

    M E Ewen

  11. Broad Institute of Harvard and MIT, Cambridge, MA, USA

    D A Barbie

  12. Division of Electrical Engineering and Computer Science, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Ishikawa, Japan

    O Hirose

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Correspondence to C Takahashi.

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Kitajima, S., Yoshida, A., Kohno, S. et al. The RB–IL-6 axis controls self-renewal and endocrine therapy resistance by fine-tuning mitochondrial activity. Oncogene 36, 5145–5157 (2017). https://doi.org/10.1038/onc.2017.124

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