Bladder cancer is the 10th most commonly diagnosed cancer worldwide. The current standard treatment for advanced bladder cancer is neoadjuvant cisplatin (NAC)-based chemotherapy followed by cystectomy. However, the response rate to chemotherapy is only 50%, owing to cisplatin resistance, and there is a need for novel therapies. Because the invasiveness of bladder cancer greatly influences patient prognosis, a mechanistic analysis of the invasive function can lead to therapeutic targets. Sialidases, which remove sialic acid residues from the nonreducing ends of sugar chains and catalyze the initial reaction in the degradation of sugar chains, are predicted to be involved in cell invasion and motility. However, the involvement of sialidases in bladder cancer, especially their relationship with the invasive ability, remains unclear. Here, using patient tissues and multiple bladder cancer cell lines, we show that the sialidase NEU3 is highly expressed in bladder cancer. Analysis of NEU3’s function using its siRNA-mediated knockdown revealed that NEU3 contributes to bladder cancer invasiveness. Mechanistic analysis showed that NEU3 activates ERK and PI3K signaling. Our results show that NEU3 is involved in the malignancy of bladder cancer, and its suppression may lead to novel treatments for bladder cancer.

Sialic acid-binding lectin from Rana catesbeiana eggs (cSBL) is a multifunctional protein that has lectin and ribonuclease activity. In this study, the anti-tumor activities of cSBL were assessed using a panel of breast cancer cell lines. cSBL suppressed the cell growth of all cancer cell lines tested here at a concentration that is less toxic, or not toxic at all, to normal cells. The growth suppressive effect was attributed to the cancer-selective induction of apoptosis. We assessed the expressions of several key molecules associated with the breast cancer phenotype after cSBL treatment by western blotting. cSBL decreased the expression level of estrogen receptor (ER) α, while it increased the phosphorylation level of p38 mitogen-activated protein kinase (MAPK). cSBL also suppressed the expression of the progesterone receptor (PgR) and human epidermal growth factor receptor type 2 (HER2). Furthermore, it was revealed that cSBL decreases the expression of the epidermal growth factor receptor (EGFR/HER1) in triple-negative breast cancer cells. These results indicate that cSBL induces apoptosis with decreasing ErbB family proteins and may have great potential for breast cancer chemotherapy, particularly in triple-negative phenotype cells.

Metastatic renal cell carcinoma (RCC) is not sufficiently responsive to anticancer drugs, and thus, developing new drugs for advanced RCC remains vital. We previously reported that the treatment of globotriaosylceramide (Gb3)-expressing cells with catfish (Silurus asotus) egg lectin (SAL) increased the intracellular uptake of propidium iodide (PI) and sunitinib (SU). Herein, we investigated whether SAL pretreatment affects the intracellular uptake and cytotoxic effects of molecular-targeted drugs in RCC cells. We analyzed Gb3 expression in TOS1, TOS3, TOS3LN, and ACHN human RCC cells. Surface Gb3 expression was higher in TOS1 and TOS3 cells than in TOS3LN and ACHN cells. In the PI uptake assay, 41.5% of TOS1 cells and 21.1% of TOS3 cells treated with SAL were positive for PI. TOS1 cell viability decreased to 70% after treatment with 25 µM SU alone and to 48% after pretreatment with SAL (50 µg/mL). Time-series measurements of the intracellular fluorescence of SU revealed significantly enhanced SU uptake in SAL-treated TOS1 cells compared to control cells. SAL treatment did not increase PI uptake in normal renal cells. Our findings suggest that adequate cytotoxic activity may be achieved even when SU is administered at a sufficiently low dose not to cause side effects in combination with SAL.

Editorial: Drug-resistance in cancer cells: A new wine in an old bottle

Silurus asotus (Amur catfish) egg lectin (SAL) inhibits cell proliferation and enhances the effects of anticancer drugs by binding to globotriaosylceramide (Gb3) on the cell surface. Gb3 expression is typically increased in seminomas. However, its association with SAL and the underlying mechanisms remain unclear. Here, we investigated the effects of SAL on morphology, migratory ability, and integrin expression in JKT-1 cells using chromatography and mass spectrometry. Gb3 was expressed in JKT-1, an established seminoma cell line. SAL did not alter JKT-1 proliferation but increased propidium iodide uptake. Furthermore, SAL induced morphological changes and increased the expression of integrin α2 in JKT-1, but not in HeLa cells. Gb3 expression was detected in JKT-1 and HeLa cells, with high- and low-mobility bands observed. However, the low-mobility bands were more abundant in JKT-1 than in HeLa cells. The main forms of Gb3 in JKT-1 cells were high-mobility d18:1/24:0 and d18:1/24:1 and low-mobility hydroxylated Gb3. Fatty acid 2-hydroxylase was involved in the acyl chain hydroxylation of low-mobility Gb3 in JKT-1 cells and showed 5-fold higher expression in JKT-1 cells than in HeLa cells. Our findings suggest that the antitumor effects of SAL vary according to the specific Gb3 molecular species expressed in cancer cells.

Sialic acid-binding lectin from Rana catesbeiana (cSBL) is a multifunctional protein with both lectin and ribonuclease activity and is, therefore, called a leczyme. It exerts cancer cell-selective antitumor effects on a variety of cancer cells in vitro and in vivo under conditions where no undesired side effects are observed. cSBL elicits antitumor effects by degrading cellular RNA and subsequently inducing apoptosis via a pathway mediated by mitochondria and endoplasmic reticulum stress. Further, it exerts synergistic antitumor effects with other molecules such as tumor necrosis factor-related apoptosis-inducing ligand and pemetrexed. Recent studies have revealed that long-term treatment of cancer cells with cSBL causes significant pleiotropic changes in the expression profiles of several genes, including multiple genes involved in metabolic pathways. Furthermore, cSBL reduces the expression of some cancer-related molecules such as human epidermal growth factor receptors, aldo-keto reductase 1B10, and ATP-binding cassette transporter C2. The information described above is expected to lead to useful applications, such as effective regimens comprising cSBL and other drugs. These findings reveal favorable properties of cSBL as an anticancer drug, which may contribute to the development of new therapeutic strategies for cancer treatment.