ABSTRACT
After the publication of the article, an interested reader drew to the authors' attention that the Du145 'Control' migration panel in Fig. 2C appeared to overlap with the Du145 'Control' invasion panel in Fig. 5A; furthermore, two of the Du145 panels in Fig. 5A also appeared to overlap. The authors have consulted their original data, and realize that these figures were inadvertently assembled incorrectly. The corrected versions of Figs. 2 and 5, incorporating the correct data for the Du145 'Control' panel in Fig. 2C, and the TQ/TGFß OE invasion and migration panels, and the TQ+/TGFß OE+ migration panel, in Fig. 5A, are shown on the next page. These further corrections do not grossly affect the results or the conclusions reported in this work. The authors all agree to this Corrigendum, and are grateful to the Editor of Oncology Reports for granting them the opportunity to correct the errors that were made during the assembly of these figures. Lastly, the authors apologize to the readership for any inconvenience these errors may have caused. [Oncology Reports 38: 35923598, 2017; DOI: 10.3892/or.2017.6012].
ABSTRACT
Thymoquinone, isolated from the seeds of Nigella sativa, has exhibited antitumor properties in a variety of cancer types. However, few studies have investigated the effect of thymoquinone (TQ) on migration and invasion in renal cell carcinoma (RCC). In the present study, our results confirmed that TQ significantly inhibited the migration and invasion of the human RCC 769P and 786O cell lines, as demonstrated by wound healing and Transwell assays. Additionally, TQ upregulated the expression of Ecadherin and downregulated the expression of Snail, ZEB1 and vimentin at the mRNA and protein levels in a concentrationdependent manner. Subsequently, the phosphorylation levels of liver kinase B1 (LKB1) and AMPactivated protein kinase (AMPK) were increased upon TQ treatment. To further validate the role of LKB1/AMPK signaling, we revealed that TQmediated increase of Ecadherin level and reduction of Snail level could be further enhanced by LKB1 overexpression. Furthermore, cotreatment with the AMPK inhibitor Compound C attenuated the antimetastatic effect of TQ on RCC and partially abrogated the high expression of Ecadherin and the low expression of Snail mediated by TQ. In contrast, the AMPK activator AICAR demonstrated the opposite effect. Collectively, the present study revealed that TQ could markedly suppress the metastatic phenotype and reverse the epithelialmesenchymal transition in RCC by regulating the LKB1/AMPK signaling pathway, indicating that TQ may be a potential therapeutic candidate against RCC.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Benzoquinones/pharmacology , Biomarkers, Tumor/metabolism , Carcinoma, Renal Cell/drug therapy , Gene Expression Regulation, Neoplastic/drug effects , Kidney Neoplasms/drug therapy , Protein Serine-Threonine Kinases/metabolism , AMP-Activated Protein Kinase Kinases , Apoptosis/drug effects , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/secondary , Cell Movement/drug effects , Cell Proliferation/drug effects , Epithelial-Mesenchymal Transition , Humans , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Phosphorylation , Tumor Cells, CulturedABSTRACT
High-mobility group AT-hook 2 (HMGA2), a member of the high mobility group family, has been reported to correlate with cancer progression. However, there is no report concerning the correlation between HMGA2 and metastasis in renal cell carcinoma. In the present study, we found that HMGA2 was highly expressed in five renal cell carcinoma cell lines compared with that in the normal renal tubular epithelial HK2 cell line. Additionally, HMGA2 facilitated cell migration and invasion of renal cell carcinoma cells, as evidenced by wound healing and Transwell assays. Subsequently, our results revealed that the Ecadherin level was upregulated, while Ncadherin, Twist1 and Twist2 expression were downregulated in HMGA2-depleted ACHN cells. In contrast, overexpression of HMGA2 in 786O cells enhanced epithelial-mesenchymal transition (EMT). In addition, analysis of the database Cancer Browser further validated the positive correlation between HGMA2 and Twist1 or Twist2 in renal cell carcinoma. Meanwhile, Kaplan-Meier analysis indicated that low HMGA2 expression was closely associated with an increased overall survival in renal cell carcinoma patients. To confirm the underlying mechanism of HMGA2-regulated EMT, our results revealed that silencing of HMGA2 downregulated the mRNA and protein levels of TGF-ß and Smad2, while HMGA2 overexpression had the opposite effect. Furthermore, TGF-ß overexpression could partially reverse the anti-metastatic effect and mesenchymal-epithelial transition (MET) by HMGA2 loss, while TGF-ß deficiency impeded the prometastatic phenotype and high expression of EMT markers induced by HMGA2 overexpression. In summary, our results demonstrated that HMGA2 facilitated a metastatic phenotype and the EMT process in renal cell carcinoma cells in vitro through a TGF-ß-dependent pathway. In addition, these data strongly suggest that HGMA2 may serve as a potential therapeutic target and prognostic biomarker against renal cell carcinoma in the future.
Subject(s)
Carcinoma, Renal Cell/metabolism , HMGA2 Protein/metabolism , Kidney Neoplasms/metabolism , Smad2 Protein/metabolism , Transforming Growth Factor beta/metabolism , Carcinoma, Renal Cell/genetics , Cell Line, Tumor , Cell Movement , Epithelial-Mesenchymal Transition , Gene Expression Regulation, Neoplastic , Humans , Kaplan-Meier Estimate , Kidney Neoplasms/genetics , Neoplasm Invasiveness , Signal Transduction , Smad2 Protein/genetics , Transforming Growth Factor beta/genetics , Up-RegulationABSTRACT
Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the roots of Stephania tetrandra is a traditional Chinese medicine and exerts anticancer capacity in various types of cancers. Previous studies have shown that tetrandrine induces apoptosis in bladder cancer cells via activation of the caspase cascade. However, the underlying mechanism has not yet been reported. Autophagy is a cellular process involved in the degradation of broken proteins and aging organelles to maintain homeostasis. Recent studies indicate that autophagy is implicated in cancer therapy. Thus, we focused on the correlation between autophagy and apoptosis upon tetrandrine treatment in human bladder cancer cells. Firstly, our results observed a marked increase in autophagic double-membrane vacuoles and fluorescent puncta of red fluorescence protein-green fluorescence protein-LC3 (GRP-RFP-LC3) upon tetrandrine treatment, as evidenced by transmission electron microscopy and confocal fluorescence microscopy. Secondly, the expression of LC3-II was increased in tetrandrine-treated T24 and 5637 cells in a time- and concentration-dependent manner. Subsequently, downregulation of p62 and LC3 turnover assay further confirmed that tetrandrine induced autophagic flux in bladder cancer T24 and 5637 cells. Thirdly, the protein levels of phosphorylated-AMP-activated protein kinase (AMPK) and phosphorylated-acetyl-coenzyme A carboxylase (ACC) were upregulated in the tetrandrine-treated cells, while the mammalian target of rapamycin (mTOR)-related proteins were downregulated. Moreover, AICAR, a common AMPK activator, further increased the expression the LC3-II, while AMPK inhibitor compound C partially reversed the LC3-II protein levels in bladder cancer T24 cells. Finally, AICAR significantly reinforced the growth inhibition and apoptosis induction of tetrandrine in T24 and 5637 cells, while compound C had an opposite effect, suggesting that AMPK-mediated autophagy enhanced the cytotoxic and pro-apoptosis effect of tetrandrine in human bladder cancer cells. Taken together, the present study showed that tetrandrine induced autophagy in human bladder cancer cells by regulating the AMPK/mTOR signaling pathway, which contributed to the apoptosis induction by tetrandrine, indicating that tetrandrine may be a potential anticancer candidate for the treatment of bladder cancer, and autophagy may be a possible mechanism for cancer therapy.
Subject(s)
Autophagy/drug effects , Benzylisoquinolines/administration & dosage , Protein Kinases/genetics , TOR Serine-Threonine Kinases/genetics , Urinary Bladder Neoplasms/drug therapy , AMP-Activated Protein Kinase Kinases , Aminoimidazole Carboxamide/administration & dosage , Aminoimidazole Carboxamide/analogs & derivatives , Apoptosis/drug effects , Autophagy/genetics , Cell Line, Tumor , Cell Survival/drug effects , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Microtubule-Associated Proteins/genetics , Protein Kinases/drug effects , Ribonucleotides/administration & dosage , Signal Transduction/drug effects , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathologyABSTRACT
Thymoquinone, a major ingredient of black seed oil (Nigella sativa), has been shown to exhibit anticancer capacity in various types of cancers. However, there are few studies concerning the correlation between thymoquinone and epithelial-to-mesenchymal transition (EMT) in prostate cancer. In the present study, we firstly found that thymoquinone showed antimetastatic capacity in prostate cancer DU145 and PC3 cells. Additionally, thymoquinone reversed EMT by increasing E-cadherin expression and decreasing vimentin and Slug expression in a concentration-dependent manner. Recent studies have shown that the transforming growth factor-ß (TGF-ß) signaling pathway may be associated with EMT. Intriguingly, the expression of TGF-ß, Smad2 and Smad3 at the mRNA and protein levels was notably reduced upon thymoquinone treatment in prostate cancer DU145 and PC3 cells. Subsequently, we confirmed that thymoquinone repressed metastasis and EMT of prostate cancer through downregulation of the TGF-ß/Smad2/3 signaling pathway, which may be partially reversed by TGF-ß overexpression. In summary, our findings demonstrated that thymoquinone suppressed the metastatic phenotype and reversed EMT of prostate cancer cells by negatively regulating the TGF-ß/Smad2/3 signaling pathway. These findings suggest that thymoquinone is a potential therapeutic agent against prostate cancer which functions by targeting TGF-ß.