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Long non-coding RNA TCL6 enhances preferential toxicity of paclitaxel to renal cell carcinoma cells.

ABSTRACT: Background: Recent findings have shown long non-coding RNAs (lncRNAs) are dysregulated in a variety of cancer cells. In this report, we investigate the effect of T-cell leukemia lymphoma 6 (TCL6) on paclitaxel (PTX)-induced apoptosis in Renal cell carcinoma (RCC) cells. Methods: Expression levels of TCL6 in RCC tissues were analyzed via The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Fluorescence in situ hybridization (FISH) was performed to detect the expression of TCL6 in RCC tissues and cells. Two pairs of cell lines were used: TCL6-silenced 786-O cell line and scrambled 786-O cell line, TCL6-overexpressed Caki-1 cell line and Caki-1 scrambled cell line. Cell viability was detected using the MTT assay. Apoptosis was examined by flow cemetery. Dual reporter gene assay was performed to confirm the direct downstream target miRNA of TCL6. Results: Based on RNA sequencing expression data of RCC tissues from TCGA and GEO datasets, the expression deficiency of TCL6 was observed in RCC tissues. Low level of TCL6 was associated with worse overall and disease-free survival of RCC patients. The FISH showed similar results with low expression of TCL6 in RCC tissues and cells. After PTX treatment, a time-dependent decrease in cell viability was observed in TCL6-overexpressed RCC cells and an increase in cell viability was observed in TCL6-silenced cells compared to control cells. Apoptosis induced by PTX was significantly increased in TCL6-overexpressed cells. Inhibition of TCL6 showed a significant decrease in apoptosis. Furthermore, luciferase reporter assay revealed that TCL6 is a direct target gene of miR-221. Conclusions: TCL6 effectively sensitizes RCC to PTX mainly through downregulation of miR-221. Our results suggest that PTX combined with TCL6 might be a potentially more effective chemotherapeutic approach for renal cancer.

SUBMITTER: Chen Z

PROVIDER: S-EPMC6995388 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Long non-coding RNA TCL6 enhances preferential toxicity of paclitaxel to renal cell carcinoma cells.

Chen Zhizhao Z Zhuang Quan Q Cheng Ke K Ming Yingzi Y Zhao Yujun Y Ye Qifa Q Zhang Sheng S

Journal of Cancer 20200101 6

<b>Background:</b> Recent findings have shown long non-coding RNAs (lncRNAs) are dysregulated in a variety of cancer cells. In this report, we investigate the effect of T-cell leukemia lymphoma 6 (TCL6) on paclitaxel (PTX)-induced apoptosis in Renal cell carcinoma (RCC) cells. <b>Methods:</b> Expression levels of TCL6 in RCC tissues were analyzed via The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Fluorescence in situ hybridization (FISH) was performed to detect the ex ...[more]

PMID: 32047545

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Project description:BackgroundPaclitaxel, a widely used chemotherapeutic drug, can induce apoptosis in variety of cancer cells. A previous study has shown preferential toxicity of paclitaxel to FLCN-deficient kidney cancer cell line, UOK257. In this report, we investigate the cellular and molecular mechanism of paclitaxel-induced autophagy and apoptosis in renal cancer cells with and without FLCN expression.MethodsTwo pairs of cell lines were used: FLCN siRNA-silenced ACHN cell line (ACHN-5968) and scrambled ACHN cell line (ACHN-sc); FLCN-null UOK257 cell line and UOK257-2 cell line restored with ectopic expression of FLCN. Autophagy was examined by western blot, GFP-LC3, transmission electron microscopy, and MDC assay. Cell viability and apoptosis were detected using MTT assay, DAPI stain and TUNEL assay. After inhibition of autophagy with 3-Methyladenine (3-MA) or Beclin 1 siRNA, cell viability and apoptosis were measured by MTT assay and TUNEL assay.ResultsAfter paclitaxel treatment, a dose-dependent decrease in cell viability and increase in apoptosis were observed in FLCN-deficient UOK257 and ACHN-5968 cells compared to their FLCN-expressing counterparts, suggesting that renal cancer cells without FLCN were more sensitive to paclitaxel. Enhanced autophagy was found to be associated with paclitaxel treatment in FLCN-deficient RCC cells. The MAPK pathway was also identified as a key pathway for the activation of autophagy in these kidney cancer cells. Inhibition of phosphorylated ERK with ERK inhibitor U0126 showed a significant decrease in autophagy. Furthermore, after inhibition of autophagy with 3-Methyladenine (3-MA) or Beclin 1 siRNA, apoptosis induced by paclitaxel was significantly increased in FLCN-deficient UOK257 and ACHN-5968 cells.ConclusionsPreferential toxicity of paclitaxel to FLCN-deficient kidney cancer cells is associated with enhanced autophagy. Suppression of autophagy further enhances paclitaxel-induced apoptosis in FLCN-deficient renal cancer cells. Our results suggest that paclitaxel combined with an autophagy inhibitor might be a potentially more effective chemotherapeutic approach for FLCN-deficient renal cancer.

Dataset Information

Long non-coding RNA TCL6 enhances preferential toxicity of paclitaxel to renal cell carcinoma cells.

Publications

Long non-coding RNA TCL6 enhances preferential toxicity of paclitaxel to renal cell carcinoma cells.

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