Inhibition of Transient Receptor Potential Channel 5 Reverses 5-Fluorouracil Resistance in Human Colorectal Cancer Cells

Wang, Teng; Chen, Zhen; Zhu, Yifei; Pan, Qiongxi; Liu, Yanjun; Qi, Xiaowei; Jin, Lei; Jin, Jian; Ma, Xin; Hua, Dong

doi:10.1074/jbc.m114.590364

Cited by 84 publications

(81 citation statements)

References 40 publications

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“…It has been reported that the expression of P-gp is up-regulated in 5-FU chemoresistant colon cancer cells [22]. The failure of 5-FU treatment of HCT 116 p53−/− cells in condition of pL3 silencig (MTT, TMRE and clonogenic assay and [15]) prompted us to investigate whether the molecular mechanisms underlying L3-mediated enhancement of 5-FU activity involved alteration in P-gp production.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of 5-FU sensitivity by the proapoptotic rpL3 gene in p53 null colon cancer cells through combined polymer nanoparticles

et al. 2016

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Colon cancer is one of the leading causes of cancer-related death worldwide and the therapy with 5-fluorouracil (5-FU) is mainly limited due to resistance. Recently, we have demonstrated that nucleolar stress upon 5-FU treatment leads to the activation of ribosome-free rpL3 (L3) as proapoptotic factor. In this study, we analyzed L3 expression profile in colon cancer tissues and demonstrated that L3 mRNA amount decreased with malignant progression and the intensity of its expression was inversely related to tumor grade and Bcl-2/Bax ratio. With the aim to develop a combined therapy of 5-FU plus plasmid encoding L3 (pL3), we firstly assessed the potentiation of the cytotoxic effect of 5-FU on colon cancer cells by L3. Next, 10 μM 5-FU and 2 μg of pL3 were encapsulated in biocompatible nanoparticles (NPs) chemically conjugated with HA to achieve active tumor-targeting ability in CD44 overexpressing cancer cells. We showed the specific intracellular accumulation of NPs in cells and a sustained release for 5-FU and L3. Analysis of cytotoxicity and apoptotic induction potential of combined NPs clearly showed that the 5-FU plus L3 were more effective in inducing apoptosis than 5-FU or L3 alone. Furthermore, we show that the cancer-specific chemosensitizer effect of combined NPs may be dependent on L3 ability to affect 5-FU efflux by controlling P-gp (P-glycoprotein) expression. These results led us to propose a novel combined therapy with the use of 5-FU plus L3 in order to establish individualized therapy by examining L3 profiles in tumors to yield a better clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

Enhancement of 5-FU sensitivity by the proapoptotic rpL3 gene in p53 null colon cancer cells through combined polymer nanoparticles

et al. 2016

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“…1C), which indicated that the increase of total b-catenin expression led to the nuclear accumulation of b-catenin rather than inducing the phosphorylation of PTEN, leading to activation of PI3K/Akt signaling, resulting in the stabilization and nuclear translocation of b-catenin [24]. It has been reported that b-catenin translocates to and accumulates in the nucleus, where it activates the expression of T-cell factor/lymphoid enhancer factor (TCF/LEF), and promotes the expression of downstream target genes, such as c-myc, MMP-7, COX-2, MRP1, and cyclin D1 [25]. To test this possibility in our model, we assessed the protein expression of c-myc and cyclin D1 while treating transfected cells with PTX, and found that they increased with increasing PTX concentration (Fig.…”

Section: Induction Of Ctnnb1 Ires Activity and Downstream Factor Protmentioning

confidence: 99%

β-Catenin expression is regulated by an IRES-dependent mechanism and stimulated by paclitaxel in human ovarian cancer cells

Chen

Gong

et al. 2015

Biochemical and Biophysical Research Communications

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“…For example, TrpC1 and TrpC3 are involved in the proliferation of breast and ovarian cancer cells, respectively (16,17), while TrpC6 is involved in the proliferation of liver and prostate tumor cells (18,19). Previously, we found that TrpC5-mediated Ca 2+ -entry induced chemoresistance in CRC via activating the Wnt/β-catenin signaling pathway (20), and the latter was demonstrated to upregulate glycolysis in CRC (21). To date, there is still no study concerning the role of Ca 2+ signaling in the regulation of glycolysis, and the detailed mechanism by which TrpC5 induces chemoresistance also deserves exploration.…”

Section: Introductionmentioning

confidence: 99%

Elevated expression of TrpC5 and GLUT1 is associated with chemoresistance in colorectal cancer

Wang

Ning

et al. 2016

Oncology Reports

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Reprogramming of energy metabolism (aerobic glycolysis) is thought to play an essential role in cancer. Compared to oxidative phosphorylation, aerobic glycolysis consumes more glucose through the upregulation of glucose transporters, notably glucose transporter 1 (GLUT1). Elevated glycolysis occurs in chemoresistant cancer cells, but the detailed mechanism is not well understood. The upregulation of the Ca2+-permeable transient receptor potential channel 5 (TrpC5) activates the Wnt/β-catenin signaling pathway in 5-fluorouracil (5-Fu)-resistant human colorectal cancer (CRC) HCT-8 (HCT-8/5-Fu) cells. In the present study, TrpC5 was overexpressed at the mRNA and protein levels along with GLUT1 in HCT-8/5-Fu cells. Suppression of TrpC5 expression with a TrpC5-specific shRNA reduced the induction of GLUT1 in the HCT-8 cells. The inhibition of the Wnt/β-catenin signaling pathway with XAV939 resulted in a decreased GLUT1 and nuclear c-Myc expression. Further study using clinical specimens validated the positive correlation between TrpC5 and GLUT1 protein levels and showed that a high TrpC5/GLUT1 expression was significantly correlated with chemoresistance. Taken together, we demonstrated the essential role of TrpC5 in GLUT1 induction and revealed that a high TrpC5/GLUT1 expression is associated with chemoresistance in human CRC.

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Inhibition of Transient Receptor Potential Channel 5 Reverses 5-Fluorouracil Resistance in Human Colorectal Cancer Cells

Cited by 84 publications

References 40 publications

Enhancement of 5-FU sensitivity by the proapoptotic rpL3 gene in p53 null colon cancer cells through combined polymer nanoparticles

Enhancement of 5-FU sensitivity by the proapoptotic rpL3 gene in p53 null colon cancer cells through combined polymer nanoparticles

β-Catenin expression is regulated by an IRES-dependent mechanism and stimulated by paclitaxel in human ovarian cancer cells

Elevated expression of TrpC5 and GLUT1 is associated with chemoresistance in colorectal cancer

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