Bladder cancer (BC) is the most popular malignant urinary cancer in China. BC has the highest incidence and mortality among all genitourinary system tumors. Although the early-stage BC could be treated with advanced electron flexible systourethroscope, early metastasis of the BC occur frequently, and often results in poor prognosis. Recently, we reported that small ubiquitin related modifier (SUMO)-specific protease 2 (SENP2) was downregulated in BC specimen. SENP2 appeared to inhibit migration and invasion of bladder cancer cells in vitro, through suppressing MMP13 in BC cells. However, the exact underlying mechanisms remain unknown. Here, we reported that SENP2 inhibited nuclear translocation of β-catenin, which targeted the promotor of MMP13 to activate MMP13 to enhance BC cell metastasis. WNT ligands induced TBL1/TBLR1 SUMOylation to form complexes with β-catenin to facilitate β-catenin nuclear translocation, which could be efficiently inhibited through suppression of SUMOylation of TBL1/TBLR1. Together, our data suggest that SENP2 inhibits MMP13 expression in BC cells through de-SUMOylation of TBL1/TBLR1, which inhibits nuclear translocation of β-catenin. Thus, SENP2 may be a promising therapeutic target for BC.
Background
In the pathogenesis and progression of prostate cancer, cell proliferation and cell migration results in tumor invasion and metastasis that is associated with patient morbidity and mortality. Rho-associated protein kinase (ROCK) has previously been shown to be upregulated in prostate cancer, but its biological role remains poorly understood. This study aimed to investigate the role of ROCK in the proliferation and migration of PC-3 and DU145 prostate cancer cells and to identify the possible targets involved by knockdown of ROCK1 and ROCK2 RNA expression.
Material/Methods
An RNA interference (RNAi) assay was performed to silence the expression of ROCK1 and ROCK2 in the PC-3 and DU145 human prostate cancer cell lines. Cells were also treated with a specific ROCK inhibitor, Y27632. A cell counting kit-8 (CCK-8) assay was used to determine the proliferation rate of prostate cancer cells, and cell migration and invasion assays were performed. Western blot and polymerase chain reaction were used to measure protein and RNA expression levels.
Results
In PC-3 and DU145 prostate cancer cells, knockdown of ROCK1 and ROCK2 reduced cell migration and invasion. ROCK1 and ROCK2 regulated cell proliferation in PC-3 and DU145 prostate cancer cells. Protein levels of phosphorylated LIM kinase 1 (p-LIMK1) and matrix metalloproteinase-2 (MMP-2) were reduced in ROCK1 and ROCK2 siRNA transfected cells.
Conclusions
In PC-3 and DU145 human prostate cancer cells, ROCK promoted cell proliferation and migration by targeting LIMK1 and MMP-2.
We profiled receptor tyrosine kinase pathway activation and key gene mutations in eight human lung tumor cell lines and 50 human lung tumor tissue samples to define molecular pathways. A panel of eight kinase inhibitors was used to determine whether blocking pathway activation affected the tumor cell growth. The HER1 pathway in HER1 mutant cell lines HCC827 and H1975 were found to be highly activated and sensitive to HER1 inhibition. H1993 is a c-MET amplified cell line showing c-MET and HER1 pathway activation and responsiveness to c-MET inhibitor treatment. IGF-1R pathway activated H358 and A549 cells are sensitive to IGF-1R inhibition. The downstream PI3K inhibitor, BEZ-235, effectively inhibited tumor cell growth in most of the cell lines tested, except the H1993 and H1650 cells, while the MEK inhibitor PD-325901 was effective in blocking the growth of KRAS mutated cell line H1734 but not H358, A549 and H460. Hierarchical clustering of primary tumor samples with the corresponding tumor cell lines based on their pathway signatures revealed similar profiles for HER1, c-MET and IGF-1R pathway activation and predict potential treatment options for the primary tumors based on the tumor cell lines response to the panel of kinase inhibitors.
Context:
Bladder cancer, which has high recurrence, is one of the most deadly cancers in the world.
Astragalus propinquus
Schischkin (Fabaceae) and
Sagittaria sagittifolia
L. (Alismataceae) are important herbs reported to be effective in cancer therapy.
Objective:
The efficacy of QCSL (Qici Sanling decoction) in bladder cancer treatment was examined.
Materials and methods:
T24 cells were injected into the flanks of nude mice and the mice were randomly divided into five groups: control; 20 mg/kg XAV-939 (an inhibitor of the WNT/β-catenin pathway); QCSL (100, 200, or 400 mg/kg). After 7 weeks, the mice were anaesthetised using isoflurane and the xenografts were excised to perform further experiments.
Results:
Both XAV-939 (tumour volume: 379.67 ± 159.92 mm
3
) and QCSL (796.18 ± 101.6 mm
3
) dramatically suppressed tumour growth comparing with control group (3612.12 ± 575.03 mm
3
). XAV-939 and QCSL treatments decreased cell proliferation from 56.3 ± 0.05% to 29.02 ± 0.07% and 37.51 ± 0.04%, respectively. In agreement, more infiltration of immune cells and pyknotic cells upon XAV-939 (apoptosis rates: 43.92 ± 0.03%) and QCSL (34.57 ± 0.04%) treatment comparing with control group (15.59 ± 0.03%) were observed. Furthermore, TUNEL staining of xenograft tumours illustrated more apoptotic cells upon XAV-939 and QCSL treatment. Mechanistically, XAV-939 and QCSL treatments significantly inhibited WNT/β-catenin pathway in T24 xenograft tumours.
Discussion and conclusions:
Our findings give new insights into the role of QCSL in bladder cancer and explore potential mechanisms contributing to the therapeutic effects of QCSL in bladder cancer.
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