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

24 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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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