TY - JOUR
T1 - Heparanase enhances tumor growth and chemoresistance by promoting autophagy
AU - Shteingauz, Anna
AU - Boyango, Ilanit
AU - Naroditsky, Inna
AU - Hammond, Edward
AU - Gruber, Maayan
AU - Doweck, Ilana
AU - Ilan, Neta
AU - Vlodavsky, Israel
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/9/15
Y1 - 2015/9/15
N2 - Heparanase is the only enzyme in mammals capable of cleaving heparan sulfate, an activity implicated in tumor inflammation, angiogenesis, and metastasis. Heparanase is secreted as a latent enzyme that is internalized and subjected to proteolytic processing and activation in lysosomes. Its role under normal conditions has yet to be understood. Here, we provide evidence that heparanase resides within autophagosomes, where studies in heparanase-deficient or transgenic mice established its contributions to autophagy. The protumorigenic properties of heparanase were found to be mediated, in part, by its proautophagic function, as demonstrated in tumor xenograft models of human cancer and through use of inhibitors of the lysosome (chloroquine) and heparanase (PG545), both alone and in combination. Notably, heparanase-overexpressing cells were more resistant to stress and chemotherapy in a manner associated with increased autophagy, effects that were reversed by chloroquine treatment. Collectively, our results establish a role for heparanase in modulating autophagy in normal and malignant cells, thereby conferring growth advantages under stress as well as resistance to chemotherapy.
AB - Heparanase is the only enzyme in mammals capable of cleaving heparan sulfate, an activity implicated in tumor inflammation, angiogenesis, and metastasis. Heparanase is secreted as a latent enzyme that is internalized and subjected to proteolytic processing and activation in lysosomes. Its role under normal conditions has yet to be understood. Here, we provide evidence that heparanase resides within autophagosomes, where studies in heparanase-deficient or transgenic mice established its contributions to autophagy. The protumorigenic properties of heparanase were found to be mediated, in part, by its proautophagic function, as demonstrated in tumor xenograft models of human cancer and through use of inhibitors of the lysosome (chloroquine) and heparanase (PG545), both alone and in combination. Notably, heparanase-overexpressing cells were more resistant to stress and chemotherapy in a manner associated with increased autophagy, effects that were reversed by chloroquine treatment. Collectively, our results establish a role for heparanase in modulating autophagy in normal and malignant cells, thereby conferring growth advantages under stress as well as resistance to chemotherapy.
UR - http://www.scopus.com/inward/record.url?scp=84942907310&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-15-0037
DO - 10.1158/0008-5472.CAN-15-0037
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C2 - 26249176
AN - SCOPUS:84942907310
SN - 0008-5472
VL - 75
SP - 3946
EP - 3957
JO - Cancer Research
JF - Cancer Research
IS - 18
ER -