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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Article numbere0158440
JournalPLoS One
Volume11
Issue number7
DOIs
Publication statusPublished - Jul 1 2016

Fingerprint

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)

Cite this

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.

In: PLoS One, Vol. 11, No. 7, e0158440, 01.07.2016.

Research output: Contribution to journalArticle

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. In: PLoS One. 2016 ; Vol. 11, No. 7.
@article{a999eb9d001d4ee1bb86f2a4383b4799,
title = "MPT0B098, a microtubule inhibitor, suppresses JAK2/STAT3 signaling pathway through modulation of SOCS3 stability in oral squamous cell carcinoma",
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.",
author = "Peng, {Hsuan Yu} and Cheng, {Yun Ching} and Hsu, {Yuan Ming} and Wu, {Guan Hsun} and Kuo, {Ching Chuan} and Liou, {Jing Ping} and Chang, {Jang Yang} and Jin, {Shiow Lian Catherine} and Shiah, {Shine Gwo}",
year = "2016",
month = "7",
day = "1",
doi = "10.1371/journal.pone.0158440",
language = "English",
volume = "11",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "7",

}

TY - JOUR

T1 - MPT0B098, a microtubule inhibitor, suppresses JAK2/STAT3 signaling pathway through modulation of SOCS3 stability in oral squamous cell carcinoma

AU - Peng, Hsuan Yu

AU - Cheng, Yun Ching

AU - Hsu, Yuan Ming

AU - Wu, Guan Hsun

AU - Kuo, Ching Chuan

AU - Liou, Jing Ping

AU - Chang, Jang Yang

AU - Jin, Shiow Lian Catherine

AU - Shiah, Shine Gwo

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84978034029&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978034029&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0158440

DO - 10.1371/journal.pone.0158440

M3 - Article

C2 - 27367272

AN - SCOPUS:84978034029

VL - 11

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 7

M1 - e0158440

ER -