Inhibition of IGFBP-2 improves the sensitivity of bladder cancer cells to cisplatin via upregulating the expression of maspin

Abstract

The present study aimed to reveal the association between insulin-like growth factor binding protein-2 (IGFBP-2) and the sensitivity of bladder cancer cells to cisplatin, and determine the underlying mechanism involving maspin. A total of 32 bladder cancer tissue samples were collected for analysis. Cells of the BIU87 human bladder cancer cell line were cultured and a cisplatin-resistant subline (BIU87-CisR) was established by continuous exposure of the cells to cisplatin. Targeted inhibition of IGFBP-2 in the BIU87-CisR cells was performed using small interfering RNA technology. The expression levels of IGFBP-2 and maspin in the tissue samples and cells were analyzed using reverse transcription-quantitative polymerase chain reaction and western blot analyses. Cell viability following treatment in each group was evaluated using a Cell Counting Kit-8 assay subsequent to treatment with 3 μM cisplatin. The cell cycle and apoptotic rate of the BIU87-CisR cells were analyzed using flow cytometry. Finally, maspin-overexpressing BIU87-CisR cells were used to confirm the effect of maspin on the sensitivity of the cells to cisplatin. The expression levels of IGFBP-2 in chemoresistant patients and BIU87-CisR cells were significantly increased, compared with those in the chemosensitive patients and BIU87 cells, respectively. However, the expression levels of maspin were lower in the cisplatin-resistant tissue and cells, and was enhanced by IGFBP-2 inhibition. Cisplatin (3 μM) caused marked proliferation inhibition, cell cycle arrest and apoptosis of the BIU87-CisR cells, the effect of which was enhanced by IGFBP-2 silencing. Overexpression of maspin also improved the sensitivity of the BIU87-CisR cells to cisplatin. In conclusion, inhibition of IGFBP-2 improved the sensitivity of bladder cancer cells to cisplatin by elevating the expression of maspin.

Maspin is a PTEN-Upregulated and p53-Upregulated Tumor Suppressor Gene and Acts as an HDAC1 Inhibitor in Human Bladder Cancer

“…Additional MTS and apoptosis assays revealed that ectopic maspin overexpressed in T24 (T24-Maspin) cells was more sensitive to cisplatin-induced apoptosis than mock-transfected T24 cells were (Figure 2E,F). These results are consistent with those of other studies reporting that the ectopic overexpression of maspin improved the sensitivity of bladder carcinoma cells to cisplatin [23,24]. Moreover, our study demonstrated that maspin blocked tumor growth in vivo when using xenografts of BALB/cAnN-Foxn1 NU mice (Figure 4).…”

IGFBP2 plays an important role in heat shock protein 27-mediated cancer progression and metastasis

“…The overexpression of IGFBP2 has been reported to be responsible for tamoxifen resistance and recurrence in pre-menopausal women with ERα-positive breast cancer [ 27 ]. Inhibiting IGFBP2 improves the sensitivity of bladder cancer cells to cisplatin by elevating the expression of maspin [ 29 ]. However, no previous report has defined the relationship between IGFBP2 and HCC.…”

“…All mouse experiments were approved by the Institutional Animal Care and Use Committee (IACUC), Taipei Medical University, and the methods used were in accordance with IACUC-approved guidelines. Five-week-old male Nu/Nu mice were used as the in vivo experimental model as described previously [ 28 , 29 ]. In brief, scrambled control and Hsp27-KD HepJ5 cells were suspended in PBS to a final density of 1 × 10 7 cells/ml.…”

“…The tumor dimensions and body weight were recorded twice per week. The tumor volume was calculated using the equation (L × w 2 )/2, where L and w refer to the larger and smaller dimensions obtained at each measurement, respectively [ 28 , 29 ]. After four weeks, the mice were sacrificed, and all of the tumors were excised and weighed.…”

Urinary Cytokine Profile to Predict Response to Intravesical BCG with or without HS-410 Therapy in Patients with Non–muscle-invasive Bladder Cancer

“…Likewise, IGFBP2, has been reported as an oncogenic marker in various cancers including bladder cancer (36). It has been suggested that blockage of IGFBP2 may increase the sensitivity of bladder cancer cells to chemotherapy (37). SHBG modulates the bioavailability of sex hormones.…”