Antitumor activity of hyaluronic acid synthesis inhibitor 4-methylumbelliferone in prostate cancer cells

Vinata B. Lokeshwar, Luis E. Lopez, Daniel Munoz, Andrew Chi, Samir P. Shirodkar, Soum D. Lokeshwar, Diogo O. Escudero, Neetika Dhir, Norman Altman

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119 Scopus citations

Abstract

4-Methylumbelliferone (4-MU) is a hyaluronic acid (HA) synthesis inhibitor with anticancer properties; the mechanism of its anticancer effects is unknown. We evaluated the effects of 4-MU on prostate cancer cells. 4-MU inhibited proliferation, motility, and invasion of DU145, PC3-ML, LNCaP, C4-2B, and/or LAPC-4 cells. At IC50 for HA synthesis (0.4 mmol/L), 4-MU induced >3-fold apoptosis in prostate cancer cells, which could be prevented by the addition of HA. 4-MU induced caspase-8, caspase-9, and caspase-3 activation, PARP cleavage, upregulation of Fas-L, Fas, FADD and DR4, and downregulation of bcl-2, phosphorylated bad, bcl-XL, phosphorylated Akt, phosphorylated 1KB, phosphorylated ErbB2, and phosphorylated epidermal growth factor receptor. At ICS0, 4-MU also caused >90% inhibition of NF-KB reporter activity, which was prevented partially by the addition of HA. With the exception of caveolin-1, HA reversed the 4-MU-induced downregulation of HA receptors (CD44 and RHAMM), matrix-degrading enzymes (MMP-2 and MMP-9), interleukin-8, and chemokine receptors (CXCRl, CXCR4, and CXCR7) at the protein and mRNA levels. Expression of myristoylated-Akt rescued 4-MU-induced apoptosis and inhibition of cell growth and interleukin-8, RHAMM, HAS2, CD44, and MMP-9 expression. Oral administration of 4-MU significantly decreased PC3-ML tumor growth (>3-fold) when treatment was started either on the day of tumor cell injection or after the tumors became palpable, without organ toxicity, changes in serum chemistry, or body weight. Tumors from 4-MU-treated animals showed reduced microvessel density (~3-fold) and HA expression but increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells and expression of apoptosisrelated molecules. Therefore, the anticancer effects of 4-MU, an orally bioavailable and relatively nontoxic agent, are primarily mediated by inhibition of HA signaling.

Original languageEnglish (US)
Pages (from-to)2613-2623
Number of pages11
JournalCancer Research
Volume70
Issue number7
DOIs
StatePublished - Apr 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Lokeshwar, V. B., Lopez, L. E., Munoz, D., Chi, A., Shirodkar, S. P., Lokeshwar, S. D., Escudero, D. O., Dhir, N., & Altman, N. (2010). Antitumor activity of hyaluronic acid synthesis inhibitor 4-methylumbelliferone in prostate cancer cells. Cancer Research, 70(7), 2613-2623. https://doi.org/10.1158/0008-5472.CAN-09-3185