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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)968-976
Number of pages9
JournalGastric Cancer
Volume21
Issue number6
DOIs
Publication statusPublished - Nov 1 2018

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Focal Adhesion Protein-Tyrosine Kinases
Gastrointestinal Stromal Tumors
Stromal Cells
Phosphatidylinositol 3-Kinases
Genetic Therapy
Receptor Protein-Tyrosine Kinases
Adenoviridae
Mutation
Phosphorylation
Imatinib Mesylate
Cell Line
STAT3 Transcription Factor
RNA Interference
Apoptosis

All Science Journal Classification (ASJC) codes

  • Oncology
  • Gastroenterology
  • Cancer Research

Cite this

Sugase, T., Takahashi, T., Serada, S., Fujimoto, M., Ohkawara, T., Hiramatsu, K., ... Naka, T. (2018). SOCS1 gene therapy has antitumor effects in imatinib-resistant gastrointestinal stromal tumor cells through FAK/PI3 K signaling. Gastric Cancer, 21(6), 968-976. https://doi.org/10.1007/s10120-018-0822-1

SOCS1 gene therapy has antitumor effects in imatinib-resistant gastrointestinal stromal tumor cells through FAK/PI3 K signaling. / Sugase, Takahito; Takahashi, Tsuyoshi; Serada, Satoshi; Fujimoto, Minoru; Ohkawara, Tomoharu; Hiramatsu, Kosuke; Nishida, Toshirou; Hirota, Seiichi; Saito, Yurina; Tanaka, Koji; Miyazaki, Yasuhiro; Makino, Tomoki; Kurokawa, Yukinori; Yamasaki, Makoto; Nakajima, Kiyokazu; Hanasaki, Kazuhiro; Kishimoto, Tadamitsu; Mori, Masaki; Doki, Yuichiro; Naka, Tetsuji.

In: Gastric Cancer, Vol. 21, No. 6, 01.11.2018, p. 968-976.

Research output: Contribution to journalArticle

Sugase, T, Takahashi, T, Serada, S, Fujimoto, M, Ohkawara, T, Hiramatsu, K, Nishida, T, Hirota, S, Saito, Y, Tanaka, K, Miyazaki, Y, Makino, T, Kurokawa, Y, Yamasaki, M, Nakajima, K, Hanasaki, K, Kishimoto, T, Mori, M, Doki, Y & Naka, T 2018, 'SOCS1 gene therapy has antitumor effects in imatinib-resistant gastrointestinal stromal tumor cells through FAK/PI3 K signaling', Gastric Cancer, vol. 21, no. 6, pp. 968-976. https://doi.org/10.1007/s10120-018-0822-1
Sugase, Takahito ; Takahashi, Tsuyoshi ; Serada, Satoshi ; Fujimoto, Minoru ; Ohkawara, Tomoharu ; Hiramatsu, Kosuke ; Nishida, Toshirou ; Hirota, Seiichi ; Saito, Yurina ; Tanaka, Koji ; Miyazaki, Yasuhiro ; Makino, Tomoki ; Kurokawa, Yukinori ; Yamasaki, Makoto ; Nakajima, Kiyokazu ; Hanasaki, Kazuhiro ; Kishimoto, Tadamitsu ; Mori, Masaki ; Doki, Yuichiro ; Naka, Tetsuji. / SOCS1 gene therapy has antitumor effects in imatinib-resistant gastrointestinal stromal tumor cells through FAK/PI3 K signaling. In: Gastric Cancer. 2018 ; Vol. 21, No. 6. pp. 968-976.
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T1 - SOCS1 gene therapy has antitumor effects in imatinib-resistant gastrointestinal stromal tumor cells through FAK/PI3 K signaling

AU - Sugase, Takahito

AU - Takahashi, Tsuyoshi

AU - Serada, Satoshi

AU - Fujimoto, Minoru

AU - Ohkawara, Tomoharu

AU - Hiramatsu, Kosuke

AU - Nishida, Toshirou

AU - Hirota, Seiichi

AU - Saito, Yurina

AU - Tanaka, Koji

AU - Miyazaki, Yasuhiro

AU - Makino, Tomoki

AU - Kurokawa, Yukinori

AU - Yamasaki, Makoto

AU - Nakajima, Kiyokazu

AU - Hanasaki, Kazuhiro

AU - Kishimoto, Tadamitsu

AU - Mori, Masaki

AU - Doki, Yuichiro

AU - Naka, Tetsuji

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

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