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, Joseph T. 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 - Jul 2013

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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, Joseph T.; Chang, Jang Yang.

In: Molecular Cancer Therapeutics, Vol. 12, No. 7, 07.2013, p. 1202-1212.

Research output: Contribution to journalArticle

Cheng, Yun Ching ; Liou, Jing Ping ; Kuo, Ching Chuan ; Lai, Wen Yang ; Shih, Kuang Hsing ; Chang, Chi Yen ; Pan, Wen Yu ; Tseng, Joseph T. ; 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.
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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.",
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AU - Kuo, Ching Chuan

AU - Lai, Wen Yang

AU - Shih, Kuang Hsing

AU - Chang, Chi Yen

AU - Pan, Wen Yu

AU - Tseng, Joseph T.

AU - Chang, Jang Yang

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