The Heparanase Inhibitor PG545 Attenuates Colon Cancer Initiation and Growth, Associating with Increased p21 Expression.
Heparanase activity is highly implicated in cellular invasion and tumor metastasis, a consequence of cleavage of heparan sulfate and remodeling of the extracellular matrix underlying epithelial and endothelial cells. Heparanase expression is rare in normal epithelia, but is often induced in tumors, associated with increased tumor metastasis and poor prognosis. In addition, heparanase induction promotes tumor growth, but the molecular mechanism that underlines tumor expansion by heparanase is still incompletely understood. Here, we provide evidence that heparanase down regulates the expression of p21 (WAF1/CIP1), a cyclin-dependent kinase inhibitor that attenuates the cell cycle. Notably, a reciprocal effect was noted for PG545, a potent heparanase inhibitor. This compound efficiently reduced cell proliferation, colony formation, and tumor xenograft growth, associating with a marked increase in p21 expression. Utilizing the APC Min+/-mouse model, we show that heparanase expression and activity are increased in small bowel polyps, whereas polyp initiation and growth were significantly inhibited by PG545, again accompanied by a prominent induction of p21 levels. Down-regulation of p21 expression adds a novel feature for the emerging pro-tumorigenic properties of heparanase, while the potent p21 induction and anti-tumor effect of PG545 lends optimism that it would prove an efficacious therapeutic in colon carcinoma patients.
Cancer and Vascular Biology Research Center, the Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
Preeti
P
Singh
Department of Gastroenterology, Rambam Health Care Campus and Bruce Rappaport School of Medicine, Technion, Haifa 3109601, Israel.
Alexandra
A
Blatt
Cancer and Vascular Biology Research Center, the Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
Sari
S
Feld
Department of Pathology, Rambam Health Care Campus and Bruce Rappaport School of Medicine, Technion, Haifa 3109601, Israel.
Yaniv
Y
Zohar
Department of Human Biology, University of Haifa, Haifa 31905, Israel.
Esraa
E
Saadi
Department of Human Biology, University of Haifa, Haifa 31905, Israel.
Liza
L
Barki-Harrington
Zucero Therapeutics, Darra, QLD 4076, Australia.
Edward
E
Hammond
Cancer and Vascular Biology Research Center, the Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
Neta
N
Ilan
Cancer and Vascular Biology Research Center, the Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
Israel
I
Vlodavsky
Department of Gastroenterology, Rambam Health Care Campus and Bruce Rappaport School of Medicine, Technion, Haifa 3109601, Israel. Electronic address: y_chowers@rambam.health.gov.il.
Yehuda
Y
Chowers
Department of Gastroenterology, Rambam Health Care Campus and Bruce Rappaport School of Medicine, Technion, Haifa 3109601, Israel. Electronic address: E_Half@rambam.health.gov.il.
Elizabeth
E
Half
D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D003111:Colonic Polyps / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099175:Heparanase
D050759:Cyclin-Dependent Kinase Inhibitor p21; D005966:Glucuronidase; D016328:NF-kappa B; D012503:Saponins; D051193:Toll-Like Receptors; D000099175:Heparanase; C557899:PG 545