Suppression of endoplasmic reticulum stress-induced invasion and migration of breast cancer cells through the downregulation of heparanase

Abstract

Tumor metastasis is the ultimate stage of cancer, and the primary cause of mortality in patients. Tumor cells breaking through the natural barrier consisting of the basement membrane (BM) and extracellular matrix (ECM) is the a crucial step in tumor invasion and metastasis. Thus, protecting this barrier is the key to reducing mortality. Heparanase is a mammalian endo-β-glucuronidase which has been found to promote the cleavage of heparan sulfate (HS), and plays a significant role in tumor cell invasion and metastasis. Although chemotherapeutic reagents have a strong antitumor activity, they may promote the invasion and migration of cancer cells, as has been observed during clinical treatment. Chemotherapeutic reagents can induce endoplasmic reticulum (ER) stress; in this study, we used adriamycin (ADM) and a classical ER stress inducer, tunicamycin (TM). We report that the activation of ER stress is involved in the enhanced invasion and migration ability of breast cancer cells and we hypothesized that this effect is associated with the activation of heparanase. In support of this, we used the heparanase inhibitor, OGT2115, and low molecular weight heparin (LMWH) to inhibit the expression and activity of heparanase, and we found that the invasion and migration ability of the cells was suppressed. Our findings demonstrate that heparanase inhibitors suppress breast cancer cell invasion and migration induced by ER stress, and provide a strong rationale for the development of heparanase-based therapeutics for the prevention of metastasis induced by chemotherapeutic reagents.

Combination therapy with low molecular weight heparin and Adriamycin results in decreased breast cancer cell metastasis in C3H mice

“…A number of studies have demonstrated that heparin induces the apoptosis of tumor cells (8–10), which is in accordance with the results observed in the present study. The TUNEL results demonstrated that following treatment, the tumor cells became apoptotic, in particular in the combination group (Fig.…”

Glucose-regulated protein 78 and heparanase expression in oral squamous cell carcinoma: correlations and prognostic significance

“…Tumor metastasis is the cause of death of the majority of cancer patients. Previous studies have indicated that HPA expression is regulated by P53, NF-KB, and ERS to promote invasion and metastasis [23-25]. The present study focused on the relationship between GRP78 and HPA.…”

The Role of Heparanase and Sulfatases in the Modification of Heparan Sulfate Proteoglycans within the Tumor Microenvironment and Opportunities for Novel Cancer Therapeutics

“…But, it is interesting to note that the induction of endoplasmic reticulum stress by chemotherapeutic reagents is involved in the enhanced invasion and migration ability of breast cancer cells and inhibition of heparanase (using one of these inhibitors, OGT2115) suppressed the invasion and migration ability of breast cancer cells. This provides a strong rationale for the development of heparanase-based therapeutics for the prevention of metastasis induced by chemotherapeutic reagents (161). The use of OGT2115 combined with cisplatin led to significant inhibition of cell proliferation, invasion, and migration of human nasopharyngeal cells, further suggesting that combination approaches with heparanase inhibitors may improve outcomes with existing chemotherapeutic regimens (162).…”