MPT0B098, a novel microtubule inhibitor that destabilizes the hypoxia-inducible factor-1α mRNA through decreasing nuclear-cytoplasmic translocation of RNA-binding protein HuR

Yun Ching Cheng, Jing Ping Liou, Ching Chuan Kuo, Wen Yang Lai, Kuang Hsing Shih, Chi Yen Chang, Wen Yu Pan, Ta-Chien Tseng, Jang-Yang Chang

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Microtubule inhibitors have been shown to inhibit hypoxia-inducible factor-1α (HIF-1α) expression through inhibition translation or enhancing protein degradation. Little is known of the effect of microtubule inhibitors on the stability of HIF-1α mRNA. We recently discovered a novel indoline-sulfonamide compound, 7-arylindoline-1-benzene-sulfonamide (MPT0B098), as a potent microtubule inhibitor through binding to the colchicine-binding site of tubulin. MPT0B098 is active against the growth of various human cancer cells, including chemoresistant cells with IC50 values ranging from 70 to 150 nmol/L. However, normal cells, such as human umbilical vein endothelial cells (HUVEC), exhibit less susceptibility to the inhibitory effect of MPT0B098 with IC50 of 510 nmol/L. Similar to typical microtubule inhibitors, MPT0B098 arrests cells in the G2-M phase and subsequently induces cell apoptosis. In addition, MPT0B098 effectively suppresses VEGF-induced cell migration and capillary-like tube formation of HUVECs. Distinguished from other microtubule inhibitors, MPT0B098 not only inhibited the expression levels of HIF-1α protein but also destabilized HIF-1α mRNA. The mechanism of causing unstable of HIF-1α mRNA by MPT0B098 is through decreasing RNA-binding protein, HuR, translocation from the nucleus to the cytoplasm. Notably, MPT0B098 effectively suppresses tumor growth and microvessel density of tumor specimens in vivo. Taken together, our results provide a novel mechanism of inhibiting HIF-1α of a microtubule inhibitor MPT0B098. MPT0B098 is a promising anticancer drug candidate with potential for the treatment of human malignancies.

Original languageEnglish
Pages (from-to)1202-1212
Number of pages11
JournalMolecular Cancer Therapeutics
Volume12
Issue number7
DOIs
Publication statusPublished - 2013 Jul 1

Fingerprint

Hypoxia-Inducible Factor 1
RNA-Binding Proteins
Microtubules
Messenger RNA
Sulfonamides
Inhibitory Concentration 50
Neoplasms
G2 Phase
Human Umbilical Vein Endothelial Cells
Colchicine
Protein Transport
Tubulin
Growth
Microvessels
Benzene
Cell Division
Vascular Endothelial Growth Factor A
Proteolysis
Cell Movement
Cytoplasm

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Cheng, Yun Ching ; Liou, Jing Ping ; Kuo, Ching Chuan ; Lai, Wen Yang ; Shih, Kuang Hsing ; Chang, Chi Yen ; Pan, Wen Yu ; Tseng, Ta-Chien ; Chang, Jang-Yang. / MPT0B098, a novel microtubule inhibitor that destabilizes the hypoxia-inducible factor-1α mRNA through decreasing nuclear-cytoplasmic translocation of RNA-binding protein HuR. In: Molecular Cancer Therapeutics. 2013 ; Vol. 12, No. 7. pp. 1202-1212.
@article{0be9c897c7bd41ec8f530ebfb1b74b5e,
title = "MPT0B098, a novel microtubule inhibitor that destabilizes the hypoxia-inducible factor-1α mRNA through decreasing nuclear-cytoplasmic translocation of RNA-binding protein HuR",
abstract = "Microtubule inhibitors have been shown to inhibit hypoxia-inducible factor-1α (HIF-1α) expression through inhibition translation or enhancing protein degradation. Little is known of the effect of microtubule inhibitors on the stability of HIF-1α mRNA. We recently discovered a novel indoline-sulfonamide compound, 7-arylindoline-1-benzene-sulfonamide (MPT0B098), as a potent microtubule inhibitor through binding to the colchicine-binding site of tubulin. MPT0B098 is active against the growth of various human cancer cells, including chemoresistant cells with IC50 values ranging from 70 to 150 nmol/L. However, normal cells, such as human umbilical vein endothelial cells (HUVEC), exhibit less susceptibility to the inhibitory effect of MPT0B098 with IC50 of 510 nmol/L. Similar to typical microtubule inhibitors, MPT0B098 arrests cells in the G2-M phase and subsequently induces cell apoptosis. In addition, MPT0B098 effectively suppresses VEGF-induced cell migration and capillary-like tube formation of HUVECs. Distinguished from other microtubule inhibitors, MPT0B098 not only inhibited the expression levels of HIF-1α protein but also destabilized HIF-1α mRNA. The mechanism of causing unstable of HIF-1α mRNA by MPT0B098 is through decreasing RNA-binding protein, HuR, translocation from the nucleus to the cytoplasm. Notably, MPT0B098 effectively suppresses tumor growth and microvessel density of tumor specimens in vivo. Taken together, our results provide a novel mechanism of inhibiting HIF-1α of a microtubule inhibitor MPT0B098. MPT0B098 is a promising anticancer drug candidate with potential for the treatment of human malignancies.",
author = "Cheng, {Yun Ching} and Liou, {Jing Ping} and Kuo, {Ching Chuan} and Lai, {Wen Yang} and Shih, {Kuang Hsing} and Chang, {Chi Yen} and Pan, {Wen Yu} and Ta-Chien Tseng and Jang-Yang Chang",
year = "2013",
month = "7",
day = "1",
doi = "10.1158/1535-7163.MCT-12-0778",
language = "English",
volume = "12",
pages = "1202--1212",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

MPT0B098, a novel microtubule inhibitor that destabilizes the hypoxia-inducible factor-1α mRNA through decreasing nuclear-cytoplasmic translocation of RNA-binding protein HuR. / Cheng, Yun Ching; Liou, Jing Ping; Kuo, Ching Chuan; Lai, Wen Yang; Shih, Kuang Hsing; Chang, Chi Yen; Pan, Wen Yu; Tseng, Ta-Chien; Chang, Jang-Yang.

In: Molecular Cancer Therapeutics, Vol. 12, No. 7, 01.07.2013, p. 1202-1212.

Research output: Contribution to journalArticle

TY - JOUR

T1 - MPT0B098, a novel microtubule inhibitor that destabilizes the hypoxia-inducible factor-1α mRNA through decreasing nuclear-cytoplasmic translocation of RNA-binding protein HuR

AU - Cheng, Yun Ching

AU - Liou, Jing Ping

AU - Kuo, Ching Chuan

AU - Lai, Wen Yang

AU - Shih, Kuang Hsing

AU - Chang, Chi Yen

AU - Pan, Wen Yu

AU - Tseng, Ta-Chien

AU - Chang, Jang-Yang

PY - 2013/7/1

Y1 - 2013/7/1

N2 - Microtubule inhibitors have been shown to inhibit hypoxia-inducible factor-1α (HIF-1α) expression through inhibition translation or enhancing protein degradation. Little is known of the effect of microtubule inhibitors on the stability of HIF-1α mRNA. We recently discovered a novel indoline-sulfonamide compound, 7-arylindoline-1-benzene-sulfonamide (MPT0B098), as a potent microtubule inhibitor through binding to the colchicine-binding site of tubulin. MPT0B098 is active against the growth of various human cancer cells, including chemoresistant cells with IC50 values ranging from 70 to 150 nmol/L. However, normal cells, such as human umbilical vein endothelial cells (HUVEC), exhibit less susceptibility to the inhibitory effect of MPT0B098 with IC50 of 510 nmol/L. Similar to typical microtubule inhibitors, MPT0B098 arrests cells in the G2-M phase and subsequently induces cell apoptosis. In addition, MPT0B098 effectively suppresses VEGF-induced cell migration and capillary-like tube formation of HUVECs. Distinguished from other microtubule inhibitors, MPT0B098 not only inhibited the expression levels of HIF-1α protein but also destabilized HIF-1α mRNA. The mechanism of causing unstable of HIF-1α mRNA by MPT0B098 is through decreasing RNA-binding protein, HuR, translocation from the nucleus to the cytoplasm. Notably, MPT0B098 effectively suppresses tumor growth and microvessel density of tumor specimens in vivo. Taken together, our results provide a novel mechanism of inhibiting HIF-1α of a microtubule inhibitor MPT0B098. MPT0B098 is a promising anticancer drug candidate with potential for the treatment of human malignancies.

AB - Microtubule inhibitors have been shown to inhibit hypoxia-inducible factor-1α (HIF-1α) expression through inhibition translation or enhancing protein degradation. Little is known of the effect of microtubule inhibitors on the stability of HIF-1α mRNA. We recently discovered a novel indoline-sulfonamide compound, 7-arylindoline-1-benzene-sulfonamide (MPT0B098), as a potent microtubule inhibitor through binding to the colchicine-binding site of tubulin. MPT0B098 is active against the growth of various human cancer cells, including chemoresistant cells with IC50 values ranging from 70 to 150 nmol/L. However, normal cells, such as human umbilical vein endothelial cells (HUVEC), exhibit less susceptibility to the inhibitory effect of MPT0B098 with IC50 of 510 nmol/L. Similar to typical microtubule inhibitors, MPT0B098 arrests cells in the G2-M phase and subsequently induces cell apoptosis. In addition, MPT0B098 effectively suppresses VEGF-induced cell migration and capillary-like tube formation of HUVECs. Distinguished from other microtubule inhibitors, MPT0B098 not only inhibited the expression levels of HIF-1α protein but also destabilized HIF-1α mRNA. The mechanism of causing unstable of HIF-1α mRNA by MPT0B098 is through decreasing RNA-binding protein, HuR, translocation from the nucleus to the cytoplasm. Notably, MPT0B098 effectively suppresses tumor growth and microvessel density of tumor specimens in vivo. Taken together, our results provide a novel mechanism of inhibiting HIF-1α of a microtubule inhibitor MPT0B098. MPT0B098 is a promising anticancer drug candidate with potential for the treatment of human malignancies.

UR - http://www.scopus.com/inward/record.url?scp=84880049488&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880049488&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-12-0778

DO - 10.1158/1535-7163.MCT-12-0778

M3 - Article

VL - 12

SP - 1202

EP - 1212

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 7

ER -