TY - JOUR
T1 - Antitumor activity of sulfated hyaluronic acid fragments in pre-clinical models of bladder cancer
AU - Jordan, Andre R.
AU - Lokeshwar, Soum D.
AU - Lopez, Luis E.
AU - Hennig, Martin
AU - Chipollini, Juan
AU - Yates, Travis
AU - Hupe, Marie C.
AU - Merseburger, Axel S.
AU - Shiedlin, Aviva
AU - Cerwinka, Wolfgang H.
AU - Liu, Kebin
AU - Lokeshwar, Vinata B.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - Tumor cell-derived hyaluronidase HYAL-1 degrades hyaluronic acid (HA) into angiogenic fragments (AGF: 10-12 disaccharides). AGF support tumor growth and progression. Urine and tissue HAase/HYAL-1 levels are sensitive markers for highgrade bladder cancer (BCa) and its metastasis. In preclinical models of BCa, we evaluated whether o-sulfated AGF (sHA-F) inhibits HAase activity and has antitumor activity. At IC50 for HAase activity inhibition (5-20 μg/ml [0.4-1.7 μM]), sHA-F significantly inhibited proliferation, motility and invasion of HYAL-1 expressing BCa cells (253J-Lung, HT1376, UMUC-3), P < 0.001. sHA-F did not affect the growth of HYAL-1 non-expressing BCa (5637, RT4, T24, TCCSUP) and normal urothelial (Urotsa, SV-HUC1) cells. sHA-F treatment induced apoptosis by death receptor pathway. sHA-F downregulated transcript and/or protein levels of HA receptors (CD44, RHAMM), p-AKT, β-catenin, pβ-Catenin(S552), Snail and Twist but increased levels of pβ- Catenin(T41/S45), pGSK-3α/β(S21/S9) and E-cadherin. sHA-F also inhibited CD44/ Phosphoinositide 3-kinase (PI-3K) complex formation and PI-3K activity. AGF addition or myristoylated-AKT overexpression attenuated sHA-F effects. Contrarily, HYAL- 1 expression sensitized RT4 cells to sHA-F treatment. In the 253J-L and HT1376 xenograft models, sHA-F treatment significantly inhibited tumor growth (P < 0.001), plausibly by inhibiting angiogenesis and HA receptor-PI-3K/AKT signaling. This study delineates that sHA-F targets tumor-associated HA-HAase system and could be potentially useful in BCa treatment.
AB - Tumor cell-derived hyaluronidase HYAL-1 degrades hyaluronic acid (HA) into angiogenic fragments (AGF: 10-12 disaccharides). AGF support tumor growth and progression. Urine and tissue HAase/HYAL-1 levels are sensitive markers for highgrade bladder cancer (BCa) and its metastasis. In preclinical models of BCa, we evaluated whether o-sulfated AGF (sHA-F) inhibits HAase activity and has antitumor activity. At IC50 for HAase activity inhibition (5-20 μg/ml [0.4-1.7 μM]), sHA-F significantly inhibited proliferation, motility and invasion of HYAL-1 expressing BCa cells (253J-Lung, HT1376, UMUC-3), P < 0.001. sHA-F did not affect the growth of HYAL-1 non-expressing BCa (5637, RT4, T24, TCCSUP) and normal urothelial (Urotsa, SV-HUC1) cells. sHA-F treatment induced apoptosis by death receptor pathway. sHA-F downregulated transcript and/or protein levels of HA receptors (CD44, RHAMM), p-AKT, β-catenin, pβ-Catenin(S552), Snail and Twist but increased levels of pβ- Catenin(T41/S45), pGSK-3α/β(S21/S9) and E-cadherin. sHA-F also inhibited CD44/ Phosphoinositide 3-kinase (PI-3K) complex formation and PI-3K activity. AGF addition or myristoylated-AKT overexpression attenuated sHA-F effects. Contrarily, HYAL- 1 expression sensitized RT4 cells to sHA-F treatment. In the 253J-L and HT1376 xenograft models, sHA-F treatment significantly inhibited tumor growth (P < 0.001), plausibly by inhibiting angiogenesis and HA receptor-PI-3K/AKT signaling. This study delineates that sHA-F targets tumor-associated HA-HAase system and could be potentially useful in BCa treatment.
UR - http://www.scopus.com/inward/record.url?scp=85017550155&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.10529
DO - 10.18632/oncotarget.10529
M3 - Journal articles
AN - SCOPUS:85017550155
SN - 1949-2553
VL - 8
SP - 24262
EP - 24274
JO - Oncotarget
JF - Oncotarget
IS - 15
ER -
