SOCS1 gene therapy has antitumor effects in imatinib-resistant gastrointestinal stromal tumor cells through FAK/PI3 K signaling

  • Takahito Sugase
  • Tsuyoshi Takahashi
  • Satoshi Serada
  • Minoru Fujimoto
  • Tomoharu Ohkawara
  • Kosuke Hiramatsu
  • Toshirou Nishida
  • Seiichi Hirota
  • Yurina Saito
  • Koji Tanaka
  • Yasuhiro Miyazaki
  • Tomoki Makino
  • Yukinori Kurokawa
  • Makoto Yamasaki
  • Kiyokazu Nakajima
  • Kazuhiro Hanasaki
  • Tadamitsu Kishimoto
  • Masaki Mori
  • Yuichiro Doki
  • Tetsuji Naka
Original Article
  • 138 Downloads

Abstract

Background

Most of the gastrointestinal stromal tumors (GIST) have mutations in the KIT gene, encoding a receptor tyrosine kinase. Imatinib, a receptor tyrosine kinase inhibitor, is the first-line therapy for unresectable and metastatic GISTs. Despite the revolutionary effects of imatinib, some patients are primarily resistant to imatinib and many become resistant because of acquisition of secondary mutations in KIT. This study investigated the antitumor effects of SOCS1 gene therapy, which targets several signaling pathways.

Methods

We used GIST-T1 (imatinib-sensitive) and GIST-R8 (imatinib-resistant) cells. We infected both cell lines with an adenovirus expressing SOCS1 (AdSOCS1) and examined antitumor effect and mechanisms of its agent.

Results

The latter harboured with secondary KIT mutation and had imatinib resistance > 1000-fold higher than the former cells. We demonstrated that AdSOCS1 significantly decreased the proliferation and induced apoptosis in both cell lines. Moreover, SOCS1 overexpression inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), AKT, and focal adhesion kinase (FAK) in both of them. Inhibition of JAK signaling did not affect the proliferation enough. However, inhibition of the FAK signaling with an FAK inhibitor or RNA interference significantly showed inhibitory effect on cell growth and suppressed the phosphorylation of AKT, indicating a cross-talk between the AKT and FAK pathways in both the imatinib-sensitive and imatinib-resistant GIST cells.

Conclusions

Our results indicate that the activation of FAK signaling is critical for proliferation of both imatinib-sensitive and -resistant GIST cells and the interference with FAK/AKT pathway might be beneficial for therapeutic target.

Keywords

Gastrointestinal stromal tumor SOCS1 Imatinib resistance Focal adhesion kinase Secondary KIT mutation 

Notes

Acknowledgements

This research was partially supported by the Practical Research for Innovative Cancer Control from the Japan Agency for Medical Research and Development (AMED, Grant no. 15ck0106106h0002).

Compliance with ethical standards

Human rights statement

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.

Animal studies

This article does not contain any studies with human or animal subjects performed by any of the authors.

Conflict of interest

No author has conflicts of interest that could potentially influence the described research.

Supplementary material

10120_2018_822_MOESM1_ESM.tiff (18.1 mb)
Supplementary material 1 (TIFF 18528 kb)

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Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2018

Authors and Affiliations

  • Takahito Sugase
    • 1
    • 2
    • 5
  • Tsuyoshi Takahashi
    • 1
  • Satoshi Serada
    • 2
  • Minoru Fujimoto
    • 2
  • Tomoharu Ohkawara
    • 2
  • Kosuke Hiramatsu
    • 2
  • Toshirou Nishida
    • 3
  • Seiichi Hirota
    • 4
  • Yurina Saito
    • 1
  • Koji Tanaka
    • 1
  • Yasuhiro Miyazaki
    • 1
  • Tomoki Makino
    • 1
  • Yukinori Kurokawa
    • 1
  • Makoto Yamasaki
    • 1
  • Kiyokazu Nakajima
    • 1
  • Kazuhiro Hanasaki
    • 5
  • Tadamitsu Kishimoto
    • 6
  • Masaki Mori
    • 1
  • Yuichiro Doki
    • 1
  • Tetsuji Naka
    • 2
  1. 1.Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineSuitaJapan
  2. 2.Center for Intractable DiseaseKochi UniversityNankokuJapan
  3. 3.National Cancer Center HospitalTokyoJapan
  4. 4.Department of Surgical PathologyHyogo College of MedicineNishinomiyaJapan
  5. 5.Department of SurgeryKochi UniversityNankokuJapan
  6. 6.Laboratory of Immune RegulationOsaka University Graduate School of Frontier BiosciencesSuitaJapan

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