[Retracted] Suppression of endoplasmic reticulum stress­induced invasion and migration of breast cancer cells through the downregulation of heparanase.

Following the publication of this paper, an interested reader drew to the attention of the authors and the Editorial Office that a number of the data panels shown for the cell migration assays in Figs. 1, 3, 4 and 5 contained overlapping data, such that the indicated results purportedly representing different experiments were derived from the same original sources. Furthermore, it was noted that the same scratch­wound assay data had apparently been included in four of the panels shown in Fig. 5D that were intended to represent different experiments performed under different conditions. After having investigated the matter internally, the Editor of International Journal of Molecular Medicine has decided that this paper should be retracted from the Journal on account of a lack of confidence in the presented data. The authors did not offer a satisfactory response to account for the various issues identified in these figures. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in International Journal of Molecular Medicine 31: 1234­1242, 2013; DOI: 10.3892/ijmm.2013.1292].

Knockdown of GRP78 enhances cell death by cisplatin and radiotherapy in nasopharyngeal cells.

Radiotherapy and adjuvant cisplatin chemotherapy are the mainstream approaches in the treatment of nasopharyngeal carcinoma (NPC). These have been shown to effectively improve the outcome and reduce tumor recurrence. However, radiotherapy and chemotherapy resistance during the course of treatment has become more common recently, resulting in the failure of NPC therapy. Therefore, new therapeutic strategies or adjuvant drugs are urgently needed. The current study was designed to look for new treatment strategies or auxiliary drugs in the treatment of NPC. Two human NPC cell lines, HNE1 and HNE1/DDP, were used to examine the relationship between endoplasmic reticulum stress and cell resistance to ionizing radiation (IR) and cisplatin (DDP). Cell proliferation was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Meanwhile, propidium iodide (PI) staining and PI/Annexin V staining were used to observe cell apoptosis. Finally, western blot was used to detect the endogenous expression of glucose-regulated protein 78 (GRP78) and other apoptosis-related proteins. GRP78 small interference RNA was transfected using Lipofectamine 2000. Compared with HNE1/DDP, IR and DDP increased the cell apoptosis and inhibited the cell proliferation of HNE1. Inhibition of GRP78 can reverse IR and DDP resistance in NPC cells by PI/Annexin V staining. Knockdown of GRP78 upregulates the expression of pro-apoptotic proteins and downregulates the expression of antiapoptotic proteins. These results indicate that HNE1 is more sensitive to DDP and IR than HNE1/DDP. Knockdown GRP78 can reverse IR and DDP resistance in NPC cells. Inhibition of GRP78 gives us a new target to overcome resistance to radiotherapy and chemotherapy of NPC cells. Thus, this study should be further explored in vivo and assessed for possible clinical applications.

[Effects of cisplatin combined with heparanase inhibitor on proliferation and invasion of human nasopharyngeal carcinoma cells].

This study is to investigate the effects of cisplatin combined with heparanase inhibitor OGT2115 on proliferation, invasion and migration of human nasopharyngeal carcinoma cells CNE-2 and to provide a new target for the treatment of metastasis of nasopharyngeal carcinoma. MTT assay was used to detect the cell viability of CNE-2 after exposure to different concentrations of DDP (2, 4, 8, 16 and 32 micromol x L(-1)), different concentrations of OGT2115 (0.4, 0.8, 1.6, 3.2 and 6.4 micromol x L(-1)), and DDP combined with OGT2115. Transwell assay was applied to analyze the effects of drugs on invasion and migration of human nasopharyngeal carcinoma cells. Wound healing assay was performed to detect cell migration and heparanase activity was analyzed by ELISA. MTT results showed that DDP can inhibit the proliferation of CNE-2 cells in a time and concentration-dependent manner, with an IC50 of 24.03 micromol x L(-1) at 24 h (P < 0.05), low concentration of DDP has almost no inhibitory effect on cell invasion and migration. DDP combined with OGT2115 can significantly inhibit cell invasion and migration. Inhibition of heparanase can significantly enhance anti-invasion and anti-proliferation of DDP.

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

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-ß-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.

Down-regulation of RIP1 by 2-deoxy-D-glucose sensitizes breast cancer cells to TRAIL-induced apoptosis.

TNF-related apoptosis-inducing ligand (TRAIL) appears to be a promising anticancer agent as it specifically kills a wide variety of cancer cells. However, resistance of subpopulations of cancer cells to TRAIL-induced cell death remains a major obstacle for successful treatment of cancer using TRAIL-based therapy. In this report we show that the hexokinase inhibitor 2-deoxy-d-glucose (2-DG) efficiently enhances TRAIL-induced apoptosis through downregulation of receptor-interacting protein kinase 1 (RIP1) in breast cancer cells. Although 2-DG alone did not kill breast cancer cells, it sensitized the cells to TRAIL-induced cell death. This could be efficiently inhibited by blockage of the caspase cascade, suggesting 2-DG augments TRAIL-mediated apoptotic signaling. Indeed, treatment with 2-DG resulted in upregulation of TRAIL receptor 2 (TRAIL-R2), downregulation of cIAP1 and XIAP, and reduction in RIP1. The latter appeared to play an important role in regulating sensitivity of breast cancer cells to TRAIL, in that knockdown of RIP1 recapitulated, at least in part, the effect of 2-DG on TRAIL-induced apoptosis. Taken together, these results indicate that 2-DG enhances TRAIL-induced apoptosis in breast cancer cells by multiple mechanisms including suppression of RIP1, and highlight the potential therapeutic benefit of combinations of 2-DG and TRAIL in the treatment of breast cancer.