NECTIN-4 increased the 5-FU resistance in colon cancer cells by inducing the PI3K–AKT cascade

Das, Diptikanta; Satapathy, Shakti Ranjan; Siddharth, Sumit; Nayak, Anmada; Kundu, Chanakya Nath

doi:10.1007/s00280-015-2794-8

Cited by 41 publications

(29 citation statements)

References 19 publications

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“…NPC (nasopharyngeal carcinoma) cell lines stably overexpressing miR-3188 exhibited significantly increased sensitivity to 5-FU by inactivating the (PI3K)/AKT pathway [24]. NECTIN-4 increased the resistance of colon cancer cells to 5-FU by inducing the PI3K/AKT cascade [25]. Activation of the PI3K/AKT pathway contributes to resistance to multiple cancer therapies, and is deemed a poor prognostic factor for cancers [26].…”

Section: Discussionmentioning

confidence: 99%

Knockdown of PRDX2 sensitizes colon cancer cells to 5-FU by suppressing the PI3K/AKT signaling pathway

Zhang²,

Wang

et al. 2017

Bioscience Reports

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Although, 5-Fluorouracil (5-FU) remains widely used in adjuvant therapy in patients with colon cancer, resistance to 5-FU-based chemotherapy is an important reason for treatment failure. Recent studies have reported that an enhanced reactive oxygen species (ROS) scavenging system shows drug resistance to 5-FU. Peroxiredoxin-2 (PRDX2), is an important member of the ROS scavenging system, and may be a potential target that promotes chemosensitivity to 5-FU in colon cancer. Here, we depleted PRDX2 by PRDX2-shRNA-LV transduction in two colon cancer cell lines and found that in vitro PRDX2 knockdown facilitates cell death, and apoptosis in 5-FU-treated colon cancer cells. In addition, we found that PRDX2 depletion in mice treated with 5-FU resulted in, inhibition of tumor growth, compared with mice treated with 5-FU alone. Our data also suggested that the PI3K/AKT signaling pathway links PRDX2 with 5-FU-induced apoptosis in colon cancer. Furthermore, when PRDX2 was overexpressed in colon cancer cells, we found increased p-AKT protein expression and reduced Bcl-2/Bax protein expression. PRDX2 and p-AKT protein expression were analyzed by immunohistochemistry technology in human colon carcinoma tissues. Pearson correlation coefficient is 0.873 and P<0.05. PRDX2 depletion led to reduced p-AKT expression and PI3K/AKT pathway inhibition promoted cell apoptosis in HT29 cell line. Taken together, our study suggests that decreasing the expression of PRDX2 could be a promising strategy for increasing the sensitivity of colon cancer cells to 5-FU.

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Section: Discussionmentioning

confidence: 99%

Knockdown of PRDX2 sensitizes colon cancer cells to 5-FU by suppressing the PI3K/AKT signaling pathway

Zhang²,

Wang

et al. 2017

Bioscience Reports

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“…The PI3K/Akt signaling pathway mediates resistance to 5-Fu in human malignant tumors, including colon cancer ( Shin et al, 2010 ; Chen et al, 2015 ; Das et al, 2015 ). Fig.…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-204 modulates colorectal cancer cell sensitivity in response to 5-fluorouracil-based treatment by targeting high mobility group protein A2

Shen

2016

Biology Open

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MicroRNAs (miRNAs) are a conserved class of ∼22 nucleotide RNAs that playing important roles in various biological processes including chemoresistance. Recently, many studies have revealed that miR-204 is significantly attenuated in colorectal cancer (CRC), suggesting that this miRNA may have a function in CRC. However, whether miR-204 modulates chemosensitivity to 5-fluorouracil (5-Fu) in colorectal cancer is still unclear. In our present study, we discuss this possibility and the potential mechanism exerting this effect. We identified high mobility group protein A2 (HMGA2) as a novel direct target of miR-204 and showed that miR-204 expression was decreased while HMGA2 expression was increased in CRC cell lines. Additionally, both MiR-204 overexpression and HMGA2 inhibition attenuated cell proliferation, whereas forced expression of HMGA2 partly restored the inhibitory effect of miR-204 on HCT116 and SW480 cells. Moreover, the miR-204/HMGA2 axis modulated the resistance of tumor cells to 5-Fu in HCT-116 and SW480 colon cancer cells via activation of the PI3K/AKT pathway. These results demonstrate that the miR-204/HMGA2 axis could play a vital role in the 5-Fu resistance of colon cancer cells. Taken together, our present study elucidated that miR-204 upregulated 5-Fu chemosensitivity via the downregulation of HMGA2 in colorectal cancer and provided significant insight into the mechanism of 5-Fu resistance in colorectal cancer patients. More importantly, our present study suggested that miR-204 has potential as a therapeutic strategy for 5-Fu-resistant colorectal cancer.

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“…As an embryonic protein, the Nectin-4 has been reported to be a tumor-associated antigen in breast, lung, ovarian, colon, and pancreatic cancers. 15 – 20 Fabre-Lafay et al 15 reported that positive expression of Nectin-4 was 61% in ductal breast carcinoma and 6% in lobular type, and was closely related to tumor histological type. In another report, Athanassiadou et al 16 found that a similar proportion of Nectin-4 positive expression was 63.5% in all breast carcinoma, but positive expression of Nectin-4 did not reveal any difference in all tumor histological types.…”

Section: Discussionmentioning

confidence: 99%

“… 32 , 33 Derycke et al 17 found that Nectin-4 increased the survival of drug resistance spheroids of ovarian cancer cells. In colon cancer, Das et al 20 demonstrated that increased expression of Nectin-4 was observed in 5-fluorouracil(FU)-resistant and 5-FU-exposed cells, and the significant increase in the tumor cell proliferation, migration, colony-formation and resistant to 5-FU were noted in 5-FU-resistant cells, but reverse was found after silencing of Nectin-4. Additionally, their results showed that Nectin-4 could deregulate afadin, which result in upregulation of the AKT–NF-κB pathway in colon cancer cells.…”

Section: Discussionmentioning

confidence: 99%

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Expression and clinical significance of Nectin-4 in hepatocellular carcinoma

Ma¹,

Zhang

et al. 2016

OTT

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ObjectiveNectin-4 is a member of the Nectin family of four Ca+-independent immunoglobulin-like cell adhesion molecules and implicated in cell adhesion, movement, proliferation, differentiation, polarization, and survival. The aberrant expression of Nectin-4 has been found in a variety of tumors; however, its expression in hepatocellular carcinoma (HCC) is still poorly understood. This study was to investigate the expression of Nectin-4 and its clinical significance in the patients with HCC.MethodsThe expression of Nectin-4 was assessed at mRNA and protein levels by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting assays in 20 HCC specimens and adjacent non-tumor live tissues. Furthermore, the clinical significance of Nectin-4 in 87 cases of HCC was confirmed by immunohistochemistry.ResultsThe mRNA and protein levels of Nectin-4 were higher in HCC tumor tissues than in the matched non-tumor tissues. Nectin-4 was located in the cytoplasm of tumor cells and over-expressed in 67.82% (59/87) HCC tissues by immunohistochemical staining. Positive Nectin-4 expression was significantly correlated with tumor size (P=0.029), status of metastasis (P=0.023), vascular invasion (P=0.018) and tumor-node-metastasis stage (P=0.003). In addition, Kaplan–Meier survival analysis indicated that positive Nectin-4 expression was associated with worse recurrence-free survival (RFS) and overall survival (OS) (P=0.006 and P=0.005, respectively). In multivariate analysis, Nectin-4 was an independent prognostic factor for RFS and OS in the patients with HCC.ConclusionNectin-4 is upregulated in HCC and may be a novel prognostic biomarker for the patients after surgical resection.

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NECTIN-4 increased the 5-FU resistance in colon cancer cells by inducing the PI3K–AKT cascade

Abstract: Our data suggest that NECTIN-4 is responsible for 5-FU resistance and BCNU + Resveratrol combination can be used to increase the 5-FU sensitivity.

Cited by 41 publications

References 19 publications

Knockdown of PRDX2 sensitizes colon cancer cells to 5-FU by suppressing the PI3K/AKT signaling pathway

Knockdown of PRDX2 sensitizes colon cancer cells to 5-FU by suppressing the PI3K/AKT signaling pathway

MicroRNA-204 modulates colorectal cancer cell sensitivity in response to 5-fluorouracil-based treatment by targeting high mobility group protein A2

Expression and clinical significance of Nectin-4 in hepatocellular carcinoma

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