PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death

Liu, Shuiping; Lin, Hui‐Ping; Wang, Da; Li, Qiang; Luo, Hong; Li, Guoxiong; Chen, Xiaohui; Li, Yongqiang; Chen, Peng; Zhai, Bingtao; Wang, Wengang; Zhang, Ruonan; Bi, Chen; Zhang, Mingming; Han, Xiao‐Jian; Li, Qiujie; Chen, Liuxi; Liu, Ying; Chen, Xiaying; Li, Guohua; Yu, Xiang; Duan, Ting; Jiao, Feng; Lou, Jian-Shu; Huang, Xingxing; Zhang, Qin; Pan, Ting; Yan, Lili; Jin, Tengchuan; Zhang, Wenzheng; Zhuo, Lvjia; Sun, Yitian; Xie, Tian; Sui, Xinbing

doi:10.1038/s41392-019-0087-0

Cited by 45 publications

(31 citation statements)

References 18 publications

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“…c-JUN is known as an important transcription factor involved in many carcinogenic processes, especially in cell cycle progression, 48 anti-apoptotic activity, 49 and cell proliferation, 50 and it serves as a downstream effector of the PI3K / AKT signal. 51 , 52 It was reported to be involved in many miRNAs’ regulation as a transcription factor, such as miR-374a 53 , 54 and miR-3188.…”

Section: Discussionmentioning

confidence: 99%

miR-4721, Induced by EBV-miR-BART22, Targets GSK3β to Enhance the Tumorigenic Capacity of NPC through the WNT/β-catenin Pathway

Tang

Chen

et al. 2020

Molecular Therapy - Nucleic Acids

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Nasopharyngeal carcinoma (NPC) is prevalent in East and Southeast Asia. In a previous study, Epstein-Barr virus (EBV)-miR-BART22 induces tumor metastasis and stemness and is significantly involved in NPC progression. In the present study, we observed that miR-4721 is induced by EBV-miR-BART22 through phosphatidylinositol 3-kinase (PI3K)/AKT/c-JUN/Sp1 signaling to promote its transcription. In a subsequent study, we observed that miR-4721 serves as a potential oncogenic factor promoting NPC cell cycle progression and cell proliferation in vitro and in vivo . Mechanism analysis indicated that miR-4721 directly targetes GSK3β and reduces its expression, which therefore elevates β-catenin intra-nuclear aggregation and activates its downstream cell cycle factors, including CCND1 and c-MYC. In clinical samples, miR-4721 and GSK3β are respectively observed to be upregulated and downregulated in NPC progression. Elevated expression of miR-4721 is positively associated with clinical progression and poor prognosis. Our study first demonstrated that miR-4721 as an oncogene is induced by EBV-miR-BART22 via modulating PI3K/AKT/c-JUN/Sp1 signaling to target GSK3β, which thus activates the WNT/β-catenin-stimulated cell cycle signal and enhances the tumorigenic capacity in NPC. miR-4721 may be a potential biomarker or therapeutic target in NPC treatment in the future.

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Section: Discussionmentioning

confidence: 99%

miR-4721, Induced by EBV-miR-BART22, Targets GSK3β to Enhance the Tumorigenic Capacity of NPC through the WNT/β-catenin Pathway

Tang

Chen

et al. 2020

Molecular Therapy - Nucleic Acids

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“…Thus, it is difficult to determine which one might be dominant due to the complex interactions between them. Liu et al (65) attempted to determine whether apoptosis or autophagy was the primary cause of cell death with autophagy inhibitor and pan-caspase inhibitor, but failed to consider the effect of autophagy inhibitor on apoptosis and apoptosis inhibitor on autophagy. In this regard, it is pivotal to clarify the crosstalk between apoptosis and autophagy and then determine the dominant one for cell death in future studies.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol modulates the apoptosis and autophagic death of human lung adenocarcinoma A549 cells via a p53‑dependent pathway: Integrated bioinformatics analysis and experimental validation

Fan

Yang

et al. 2020

Int J Oncol

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Resveratrol (RSV) has been reported to exhibit cytotoxic activity in multiple types of malignant cells; however, the mechanisms underlying the antitumor effects of RSV in non-small-cell lung cancer (NSCLC) cells remain undetermined. Combining bioinformatics analysis with experimental validation, the present study aimed to examine the effects of RSV on the apoptosis and autophagy of A549 NSCLC cells, and to determine the potential underlying molecular mechanisms. Bioinformatics analysis was used to determine the differentially expressed genes (DEGs) and identify the enriched biological functions and pathways associated with these DEGs following RSV treatment. Cell viability was determined by MTT assay, and flow cytometry and TUNEL assay were used to evaluate cell apoptosis. Monodansylcadaverine staining combined with a transmission electron microscope were used to evaluate the extent of autophagy. The expression levels of apoptosis-, autophagy-, or pathway-associated molecular markers were measured by reverse transcription-quantitative PCR and/or western blot analysis. By bioinformatics analysis, a total of 1,031 DEGs were identified in the RSV-treated A549 cells, which were enriched in apoptosis-, or autophagy-related biological functions and the p53 signaling pathway. In validation experiments, RSV significantly reduced cell viability and initiated apoptosis, with an increase in the number of apoptotic cells; it also upregulated cleaved caspase-3 expression and Bax expression, and downregulated the Bcl-2 expression levels. Additionally, there was an increase in the accumulation of green dot-like structures, indicative of autophagic vesicles, observed under a fluorescence microscope, and an increase in the presence of autophagic vacuoles observed using a transmission electron microscope following RSV treatment. Furthermore, the expression levels of the autophagy-related proteins, LC3-II/LC3-I and Beclin-1, were increased and p62 expression was decreased. 3-methyladenine (3-MA), an inhibitor of autophagy, partially reversed the RSV-induced cytotoxic effects, but did not significantly alter the number of apoptotic cells. RSV elevated the p53 levels and decreased the phosphorylated (p-)Mdm2 and p-Akt levels. Pifithrin-α, an inhibitor of p53, partially reduced RSV-induced apoptosis and autophagy. On the whole, the results of the present study demonstrated that RSV initiates the apoptosis and autophagic death of A549 cells via the activation of the p53 signaling pathway, further highlighting the potential of RSV for the treatment of NSCLC.

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“…PCDH17 combined with 5-FU in the treatment of colorectal cancer has also been found to induce apoptosis and autophagic cell death. In addition, autophagy played a leading role in cell death induced by PCDH17, as an autophagy inhibitor blocked cell death to better than the pan-caspase inhibitor Z -VAD-FMK [ 39 ]. However, compared with apoptosis, autophagy in promoting cell death is not always a dominant position.…”

Section: The Main Way Of Crosstalk Between Autophagy and Apoptosis Inmentioning

confidence: 99%

The interaction mechanism between autophagy and apoptosis in colon cancer

Xie

Liu

2020

Translational Oncology

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Autophagy and apoptosis play crucial roles in tumorigenesis. Recent studies have shown that autophagy and apoptosis have a cross-talk relationship in anti-tumor therapy. It is well established that apoptosis is one of the main pathways of tumor cell death. While autophagy can occurs in tumors with opposite function: protective autophagy and lethal autophagy. Protective autophagy can inhibit tumor apoptosis induced by anticancer drugs, while lethal autophagy can induce tumor cell apoptosis in cooperation with anticancer drugs. Hence, autophagy and apoptosis have synergistic and antagonistic effects in tumor. Colorectal cancer is a common malignant tumor with high morbidity and mortality. In recent years, colorectal carcinoma has achieved improved clinical efficacy with drug treatment. Nonetheless, increasing drug-resistance limit the treatment efficacy, highlighting the urgency of exploring the molecular events that drive drug resistance. Researchers have found that autophagy is one of the major factors leading to drug resistance in colon cancer. Therefore, elucidating the interaction between autophagy and apoptosis is helpful to improve the efficacy of anticancer drugs in clinical treatment of colorectal cancer. This review attaches great importance to the relationship between autophagy and apoptosis and related factors in colorectal cancer.

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PCDH17 increases the sensitivity of colorectal cancer to 5-fluorouracil treatment by inducing apoptosis and autophagic cell death

Cited by 45 publications

References 18 publications

miR-4721, Induced by EBV-miR-BART22, Targets GSK3β to Enhance the Tumorigenic Capacity of NPC through the WNT/β-catenin Pathway

miR-4721, Induced by EBV-miR-BART22, Targets GSK3β to Enhance the Tumorigenic Capacity of NPC through the WNT/β-catenin Pathway

Resveratrol modulates the apoptosis and autophagic death of human lung adenocarcinoma A549 cells via a p53‑dependent pathway: Integrated bioinformatics analysis and experimental validation

The interaction mechanism between autophagy and apoptosis in colon cancer

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