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Active Secretion of Dimerized S100A11 Induced by the Peroxisome in Mesothelioma Cells

  • Original Article
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Cancer Microenvironment

Abstract

S100A11, a small Ca2+ binding protein, acts extracellularly as a mediator of cancer progression. That raises the question of how a protein that lacks the classical secretory signal is able to be secreted outside cells without being damaged. Some insights into this question have been obtained, and there has been accumulating evidence indicating a pivotal role of a non-classical vesicle-mediated pathway using lysosomes or peroxisomes for the protein secretion. To obtain a more precise insight into the secretory mechanism of S100A11, we first screened representative cancer cells exhibiting significantly active secretion of S100A11. From the results of profiling, we turned our attention to aggressive cancer mesothelioma cells. In mesothelioma cells, we found that abundant dimeric S100A11 was produced selectively in the peroxisome after transportation of monomeric S100A11 through an interaction with PEX14, a peroxisome membrane protein, resulting in peroxisomal secretion of dimerized S100A11. In an extracellular environment in vitro, dimerized S100A11 promoted mesothelial cell invasion indirectly with the help of fibroblast cells. Overall, the results indicate that the peroxisome functions as an essential vesicle for the production of dimerized S100A11 and the subsequent secretion of the protein from mesothelioma cells and that peroxisome-mediated secretion of dimerized S100A11 might play a critical role in mesothelioma progression in a tumor microenvironment.

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Abbreviations

Ca:

Calcium

FBS:

Fetal bovine serum

DTT:

Dithiothreitol

RAGE:

Receptor for advanced glycation endproducts

HMGB1:

High mobility group box 1

HSP70:

Heat shock protein 70

IL-1β:

Interleukin-1β

ER:

Endoplasmic reticulum

HE:

Hematoxylin-eosin

ANXAI:

Annexin I

cPLA2 :

cytosolic phospholipase A2

EGFR:

Epidermal growth factor receptor

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Acknowledgements

We would like to thank Dr Midori Kitazoe from the Department of Life Science, Faculty of Science, Okayama University of Science for her kind support in providing highly purified recombinant S100A11.

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Authors and Affiliations

  1. Department of Cell Biology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama-shi, Okayama, 700-8558, Japan

    Satomi Saho, Hitoshi Murata, Rie Kinoshita, Ken-ichi Yamamoto, Endy Widya Putranto, I Made Winarsa Ruma, I Wayan Sumardika, Chen Youyi, Nam-ho Huh & Masakiyo Sakaguchi

  2. Department of Thoracic, Breast and Endocrinological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan

    Hiroki Satoh, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh & Shinichi Toyooka

  3. Division of Molecular and Cellular Pathology, Niigata University Graduate School of Medical and Dental Sciences, 757, Ichiban-cho, Asahimachi-dori, Chuo-ku, Niigata-shi, Niigata, 951-8510, Japan

    Eisaku Kondo, Ken Saito & Hidekazu iioka

  4. Faculty of Science and Technology, Division of Molecular Science, Gunma University, 1-5-1 Tenjin-cho, Kiryu-shi, Gunma, 376-8515, Japan

    Yusuke Inoue

  5. Department of Biochemistry, Kawasaki Medical School, 577 Matsushima, Kurashiki-shi, Okayama, 701-0192, Japan

    Akira Yamauchi

  6. Department of Medical and Bioengineering Science, Okayama University Graduate School of Natural Science and Technology, 3-1-1, Tsushima-Naka, Kita-ku, Okayama, 700-8530, Japan

    Junichiro Futami

  7. Department of Biobank, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan

    Shuta Tomida

  8. Department of Microbiology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami, Sagamihara, Kanagawa, 252-0374, Japan

    Yoshihiko Sakaguchi

  9. Faculty of Medicine, Gajah Mada University, Yogyakarta, 55281, Indonesia

    Endy Widya Putranto

  10. Faculty of Medicine, Udayana University, Denpasar, 80232, Bali, Indonesia

    I Made Winarsa Ruma & I Wayan Sumardika

  11. Department of Clinical Genomic Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan

    Shinichi Toyooka

Authors
  1. Satomi Saho
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  2. Hiroki Satoh
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  3. Eisaku Kondo
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  4. Yusuke Inoue
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  5. Akira Yamauchi
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  6. Hitoshi Murata
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  7. Rie Kinoshita
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  8. Ken-ichi Yamamoto
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  9. Junichiro Futami
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  10. Endy Widya Putranto
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  11. I Made Winarsa Ruma
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  12. I Wayan Sumardika
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  13. Chen Youyi
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  14. Ken Suzawa
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  15. Hiromasa Yamamoto
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  16. Junichi Soh
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  17. Shuta Tomida
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  18. Yoshihiko Sakaguchi
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  19. Ken Saito
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  20. Hidekazu iioka
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  21. Nam-ho Huh
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  22. Shinichi Toyooka
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  23. Masakiyo Sakaguchi
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Corresponding author

Correspondence to Masakiyo Sakaguchi.

Ethics declarations

Immunohistochemical studies using human tissue specimens were approved by the Research Ethics Committee in Niigata University Medical and Dental Hospital, and only samples in Niigata University Graduate School of Medicine and Dental Sciences were used. Informed consent was obtained from each patient for use of these materials.

Conflict of Interests

The authors declare that they have no conflicts of interest.

Funding

This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Grant–in-Aid for Scientific Research (B), No. 26290039; Grant–in-Aid for Challenging Exploratory Research, No. 15 K14382) (M. Sakaguchi), from the Takeda Science Foundation (M. Sakaguchi), from the Princess Takamatsu Cancer Research Fund (14–24613; M. Sakaguchi), and from the Kobayashi Foundation for Cancer Research (M. Sakaguchi).

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Saho, S., Satoh, H., Kondo, E. et al. Active Secretion of Dimerized S100A11 Induced by the Peroxisome in Mesothelioma Cells. Cancer Microenvironment 9, 93–105 (2016). https://doi.org/10.1007/s12307-016-0185-2

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  • DOI: https://doi.org/10.1007/s12307-016-0185-2

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