MPT0B098, a microtubule inhibitor, suppresses JAK2/STAT3 signaling pathway through modulation of SOCS3 stability in oral squamous cell carcinoma

Hsuan Yu Peng, Yun Ching Cheng, Yuan Ming Hsu, Guan Hsun Wu, Ching Chuan Kuo, Jing Ping Liou, Jang Yang Chang, Shiow Lian Catherine Jin, Shine Gwo Shiah

研究成果: 雜誌貢獻文章

12 引文 (Scopus)

摘要

Microtubule inhibitors have been shown to inhibit Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signal transduction pathway in various cancer cells. However, little is known of the mechanism by which the microtubule inhibitors inhibit STAT3 activity. In the present study, we examined the effect of a novel small-molecule microtubule inhibitor, MPT0B098, on STAT3 signaling in oral squamous cell carcinoma (OSCC). Treatment of various OSCC cells with MPT0B098 induced growth inhibition, cell cycle arrest and apoptosis, as well as increased the protein level of SOCS3. The accumulation of SOCS3 protein enhanced its binding to JAK2 and TYK2 which facilitated the ubiquitination and degradation of JAK2 and TYK2, resulting in a loss of STAT3 activity. The inhibition of STAT3 activity led to sensitization of OSCC cells to MPT0B098 cytotoxicity, indicating that STAT3 is a key mediator of drug resistance in oral carcinogenesis. Moreover, the combination of MPT0B098 with the clinical drug cisplatin or 5-FU significantly augmented growth inhibition and apoptosis in OSCC cells. Taken together, our results provide a novel mechanism for the action of MPT0B098 in which the JAK2/STAT3 signaling pathway is suppressed through the modulation of SOCS3 protein level. The findings also provide a promising combinational therapy of MPT0B098 for OSCC.

原文英語
文章編號e0158440
期刊PLoS One
11
發行號7
DOIs
出版狀態已發佈 - 七月 1 2016

指紋

non-specific protein-tyrosine kinase
Janus Kinase 2
STAT3 Transcription Factor
squamous cell carcinoma
Microtubules
microtubules
Squamous Cell Carcinoma
mouth
transcription (genetics)
Modulation
growth retardation
Cells
Apoptosis
apoptosis
Signal transduction
Proteins
Ubiquitination
Cytotoxicity
Growth
Cell Cycle Checkpoints

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

引用此文

MPT0B098, a microtubule inhibitor, suppresses JAK2/STAT3 signaling pathway through modulation of SOCS3 stability in oral squamous cell carcinoma. / Peng, Hsuan Yu; Cheng, Yun Ching; Hsu, Yuan Ming; Wu, Guan Hsun; Kuo, Ching Chuan; Liou, Jing Ping; Chang, Jang Yang; Jin, Shiow Lian Catherine; Shiah, Shine Gwo.

於: PLoS One, 卷 11, 編號 7, e0158440, 01.07.2016.

研究成果: 雜誌貢獻文章

Peng, Hsuan Yu ; Cheng, Yun Ching ; Hsu, Yuan Ming ; Wu, Guan Hsun ; Kuo, Ching Chuan ; Liou, Jing Ping ; Chang, Jang Yang ; Jin, Shiow Lian Catherine ; Shiah, Shine Gwo. / MPT0B098, a microtubule inhibitor, suppresses JAK2/STAT3 signaling pathway through modulation of SOCS3 stability in oral squamous cell carcinoma. 於: PLoS One. 2016 ; 卷 11, 編號 7.
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abstract = "Microtubule inhibitors have been shown to inhibit Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signal transduction pathway in various cancer cells. However, little is known of the mechanism by which the microtubule inhibitors inhibit STAT3 activity. In the present study, we examined the effect of a novel small-molecule microtubule inhibitor, MPT0B098, on STAT3 signaling in oral squamous cell carcinoma (OSCC). Treatment of various OSCC cells with MPT0B098 induced growth inhibition, cell cycle arrest and apoptosis, as well as increased the protein level of SOCS3. The accumulation of SOCS3 protein enhanced its binding to JAK2 and TYK2 which facilitated the ubiquitination and degradation of JAK2 and TYK2, resulting in a loss of STAT3 activity. The inhibition of STAT3 activity led to sensitization of OSCC cells to MPT0B098 cytotoxicity, indicating that STAT3 is a key mediator of drug resistance in oral carcinogenesis. Moreover, the combination of MPT0B098 with the clinical drug cisplatin or 5-FU significantly augmented growth inhibition and apoptosis in OSCC cells. Taken together, our results provide a novel mechanism for the action of MPT0B098 in which the JAK2/STAT3 signaling pathway is suppressed through the modulation of SOCS3 protein level. The findings also provide a promising combinational therapy of MPT0B098 for OSCC.",
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