PMID- 21555367
OWN - NLM
STAT- MEDLINE
DCOM- 20110818
LR  - 20211020
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 71
IP  - 12
DP  - 2011 Jun 15
TI  - Targeting hyaluronidase for cancer therapy: antitumor activity of sulfated 
      hyaluronic acid in prostate cancer cells.
PG  - 4085-95
LID - 10.1158/0008-5472.CAN-10-4610 [doi]
AB  - The tumor cell-derived hyaluronidase (HAase) HYAL-1 degrades hyaluronic acid (HA) 
      into proangiogenic fragments that support tumor progression. Although HYAL-1 is a 
      critical determinant of tumor progression and a marker for cancer diagnosis and 
      metastasis prediction, it has not been evaluated as a target for cancer therapy. 
      Similarly, sulfated hyaluronic acid (sHA) has not been evaluated for biological 
      activity, although it is an HAase inhibitor. In this study, we show that sHA is a 
      potent inhibitor of prostate cancer. sHA blocked the proliferation, motility, and 
      invasion of LNCaP, LNCaP-AI, DU145, and LAPC-4 prostate cancer cells, and induced 
      caspase-8-dependent apoptosis associated with downregulation of Bcl-2 and 
      phospho-Bad. sHA inhibited Akt signaling including androgen receptor (AR) 
      phosphorylation, AR activity, nuclear factor kappaB (NFkappaB) activation, and VEGF 
      expression. These effects were traced to a blockade in complex formation between 
      phosphoinositide 3-kinase (PI3K) and HA receptors and to a transcriptional 
      downregulation of HA receptors, CD44, and RHAMM, along with PI3K inhibition. 
      Angiogenic HA fragments or overexpression of myristoylated Akt or HA receptors 
      blunted these effects of sHA, implicating a feedback loop between HA receptors 
      and PI3K/Akt signaling in the mechanism of action. In an animal model, sHA 
      strongly inhibited LNCaP-AI prostate tumor growth without causing weight loss or 
      apparent serum-organ toxicity. Inhibition of tumor growth was accompanied by a 
      significant decrease in tumor angiogenesis and an increase in apoptosis index. 
      Taken together, our findings offer mechanistic insights into the tumor-associated 
      HA-HAase system and a preclinical proof-of-concept of the safety and efficacy of 
      sHA to control prostate cancer growth and progression.
FAU - Benitez, Anaid
AU  - Benitez A
AD  - Department of Urology, University of Miami Miller School of Medicine, Miami, 
      Florida 33101, USA.
FAU - Yates, Travis J
AU  - Yates TJ
FAU - Lopez, Luis E
AU  - Lopez LE
FAU - Cerwinka, Wolfgang H
AU  - Cerwinka WH
FAU - Bakkar, Ashraf
AU  - Bakkar A
FAU - Lokeshwar, Vinata B
AU  - Lokeshwar VB
LA  - eng
GR  - R01 CA 123063-04/CA/NCI NIH HHS/United States
GR  - R01 CA072821-09/CA/NCI NIH HHS/United States
GR  - R01 CA123063-02/CA/NCI NIH HHS/United States
GR  - R01 CA072821-10A2/CA/NCI NIH HHS/United States
GR  - R01 CA123063-04/CA/NCI NIH HHS/United States
GR  - R01 CA072821-11/CA/NCI NIH HHS/United States
GR  - R01 CA123063-03/CA/NCI NIH HHS/United States
GR  - R01CA72821-10/CA/NCI NIH HHS/United States
GR  - R01 CA123063/CA/NCI NIH HHS/United States
GR  - R01 CA072821/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110509
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antineoplastic Agents)
RN  - 0 (CD44 protein, human)
RN  - 0 (Hyaluronan Receptors)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 9004-61-9 (Hyaluronic Acid)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.2.1.35 (Hyaluronoglucosaminidase)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Humans
MH  - Hyaluronan Receptors/genetics
MH  - Hyaluronic Acid/*pharmacology
MH  - Hyaluronoglucosaminidase/*antagonists & inhibitors
MH  - Male
MH  - Mice
MH  - Neoplasm Invasiveness
MH  - Neovascularization, Pathologic/drug therapy
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Prostatic Neoplasms/blood/*drug therapy/pathology
MH  - Proto-Oncogene Proteins c-akt/antagonists & inhibitors
MH  - Vascular Endothelial Growth Factor A/genetics
PMC - PMC3117105
MID - NIHMS293761
EDAT- 2011/05/11 06:00
MHDA- 2011/08/19 06:00
PMCR- 2012/06/15
CRDT- 2011/05/11 06:00
PHST- 2011/05/11 06:00 [entrez]
PHST- 2011/05/11 06:00 [pubmed]
PHST- 2011/08/19 06:00 [medline]
PHST- 2012/06/15 00:00 [pmc-release]
AID - 0008-5472.CAN-10-4610 [pii]
AID - 10.1158/0008-5472.CAN-10-4610 [doi]
PST - ppublish
SO  - Cancer Res. 2011 Jun 15;71(12):4085-95. doi: 10.1158/0008-5472.CAN-10-4610. Epub 
      2011 May 9.