Heparanase enhances tumor growth and chemoresistance by promoting autophagy

Anna Shteingauz, Ilanit Boyango, Inna Naroditsky, Edward Hammond, Maayan Gruber, Ilana Doweck, Neta Ilan, Israel Vlodavsky

Research output: Contribution to journalArticlepeer-review

128 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)3946-3957
Number of pages12
JournalCancer Research
Volume75
Issue number18
DOIs
StatePublished - 15 Sep 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015 American Association for Cancer Research.

Funding

FundersFunder number
Israel Cancer Research Fund
Israel Science Foundation601/14
National Cancer Institute
National Institutes of Health
National Cancer InstituteR01CA106456

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