FFJ-3 inhibits PKM2 protein expression via the PI3K/Akt signaling pathway and activates the mitochondrial apoptosis signaling pathway in human cancer cells

ABSTRACT Viruses have evolved an assortment of mechanisms for regulating the Akt signaling pathway to establish a cellular environment more favorable for viral replication. Myxoma virus (MYXV) is a rabbit-specific poxvirus that encodes many immunomodulatory factors, including an ankyrin repeat-containing host range protein termed M-T5 that functions to regulate tropism of MYXV for rabbit lymphocytes and certain human cancer cells. MYXV permissiveness in these human cancer cells is dependent upon the direct interaction between M-T5 and Akt, which has been shown to induce the kinase activity of Akt. In this study, an array of compounds that selectively manipulate Akt signaling was screened and we show that only a subset of Akt inhibitors significantly decreased the ability of MYXV to replicate in previously permissive human cancer cells. Furthermore, reduced viral replication efficiency was correlated with lower levels of phosphorylated Akt. In contrast, the PP2A-specific phosphatase inhibitor okadaic acid promoted increased Akt kinase activation and rescued MYXV replication in human cancer cells that did not previously support viral replication. Finally, phosphorylation of Akt at residue Thr308 was shown to dictate the physical interaction between Akt and M-T5, which then leads to phosphorylation of Ser473 and permits productive MYXV replication in these human cancer cells. The results of this study further characterize the mechanism by which M-T5 exploits the Akt signaling cascade and affirms this interaction as a major tropism determinant that regulates the replication efficiency of MYXV in human cancer cells.

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Asiatic Acid Interferes with Invasion and Proliferation of Breast Cancer Cells by Inhibiting WAVE3 Activation through PI3K/AKT Signaling Pathway

BioMed Research International ◽

10.1155/2020/1874387 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Xiao-jun Gou ◽

Huan-huan Bai ◽

Li-wei Liu ◽

Hong-yu Chen ◽

Qi Shi ◽

...

Keyword(s):

Breast Cancer ◽

Protein Expression ◽

Cancer Cells ◽

Signaling Pathway ◽

Nude Mice ◽

Breast Cancer Cells ◽

Akt Signaling ◽

Asiatic Acid ◽

Akt Signaling Pathway ◽

Xenografted Tumor

Objective. To explore the ability of asiatic acid to interfere with the invasion and proliferation of breast cancer cells by inhibiting WAVE3 expression and activation through the PI3K/AKT signaling pathway. Methods. The MDA-MB-231 cells with strong invasiveness were screened by transwell assay, and plasmids with high expression of WAVE3 were constructed for transfection. The transfection effect and protein expression level of plasmids were verified by PCR and WB. The effects of asiatic acid on cell proliferation and invasion were investigated by flow cytometry. The xenografted tumor models in nude mice were established to study the antitumor activity of asiatic acid. Results. Asiatic acid significantly inhibited the activity of MDA-MB-231 cells, and the expression level of WAVE3 increased significantly in the tissue of ductal carcinoma in situ and was lower than that in the metastasis group. After plasmid transfection, the mRNA and protein expression of WAVE3 increased significantly in the cells. Asiatic acid at different concentrations had an impact on cell apoptosis and invasion and could significantly inhibit the expression of WAVE3, P53, p-PI3K, p-AKT, and other proteins. The T/C(%) of asiatic acid (50 mg/kg) for MDA-MB-231(F10) xenografted tumor in nude mice was 46.33%, with a tumor inhibition rate of 59.55%. Asiatic acid could significantly inhibit the growth of MDA-MB-231 (F10) xenografted tumors in nude mice (p<0.05). Conclusions. Asiatic acid interferes with the ability of breast cancer cells to invade and proliferate by inhibiting WAVE3 expression and activation and the mechanism of action may be related to the PI3K/AKT signaling pathway.

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Staurosporine suppresses survival of HepG2 cancer cells through Omi/HtrA2-mediated inhibition of PI3K/Akt signaling pathway

Tumor Biology ◽

10.1177/1010428317694317 ◽

2017 ◽

Vol 39 (3) ◽

pp. 101042831769431 ◽

Cited By ~ 10

Author(s):

Youming Ding ◽

Bin Wang ◽

Xiaoyan Chen ◽

Yu Zhou ◽

Jianhui Ge

Keyword(s):

Cell Death ◽

Cell Viability ◽

Cancer Cells ◽

Signaling Pathway ◽

Human Cancer ◽

Akt Signaling ◽

Therapeutic Effects ◽

Concomitant Treatment ◽

Dependent Manner ◽

Akt Signaling Pathway

Staurosporine, which is an inhibitor of a broad spectrum of protein kinases, has shown cytotoxicity on several human cancer cells. However, the underlying mechanism is not well understood. In this study, we examined whether and how this compound has an inhibitory action on phosphatidylinositol 3-kinase (PI3K)/Akt pathway in vitro using HepG2 human hepatocellular carcinoma cell line. Cell viability and apoptosis were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and terminal deoxyribonucleotidyl transferase–mediated dUTP-digoxigenin nick end labeling (TUNEL) assay, respectively. Glutathione S-transferase (GST) pull-down assay and co-immunoprecipitation were performed to detect protein–protein interactions. Small interfering RNA (siRNA) was used to silence the expression of targeted protein. We found that staurosporine significantly decreased cell viability and increased cell apoptosis in a concentration- and time-dependent manner in HepG2 cancer cells, along with the decreased expressions of PDK1 protein and Akt phosphorylation. Staurosporine was also found to enhance Omi/HtrA2 release from mitochondria. Furthermore, Omi/HtrA2 directly bound to PDK1. Pharmacological and genetic inhibition of Omi/HtrA2 restored protein levels of PDK1 and protected HepG2 cancer cells from staurosporine-induced cell death. In addition, staurosporine was found to activate autophagy. However, inhibition of autophagy exacerbated cell death under concomitant treatment with staurosporine. Taken together, our results indicate that staurosporine induced cytotoxicity response by inhibiting PI3K/Akt signaling pathway through Omi/HtrA2-mediated PDK1 degradation, and the process provides a novel mechanism by which staurosporine produces its therapeutic effects.

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TUSC3 inhibits cell proliferation and invasion in cervical squamous cell carcinoma via suppression of the AKT signaling pathway

10.21203/rs.3.rs-272307/v1 ◽

2021 ◽

Author(s):

Fei Sun ◽

Qiuling Jie ◽

Qi Li ◽

Yunjian Wei ◽

Ping Long ◽

...

Keyword(s):

Cell Proliferation ◽

Squamous Cell Carcinoma ◽

Protein Expression ◽

Cancer Cells ◽

Signaling Pathway ◽

Cervical Squamous Cell Carcinoma ◽

Akt Signaling ◽

Migration And Invasion ◽

Akt Signaling Pathway ◽

Proliferation And Invasion

Abstract Background The expression of tumor suppressor candidate 3 (TUSC3) is associated with proliferation in several types of cancer, leading to an unfavorable prognosis. The present study aimed to assess the cellular and molecular function of TUSC3 in patients with cervical squamous cell carcinoma (CSCC). Methods Levels of mRNA expressions of TUSC3 were analyzed in CSCC tissues and six cell lines using qRT-PCR. Immunohistochemistry(IHC) was used to evaluate the protein expression level of TUSC3 in four paired specimens, 220 paraffin-embedded CSCC specimens and 60 cases of normal cervical tissues(NCTs), respectively. Short hairpin RNA interference was employed for TUSC3 knockdown. Cell proliferation, migration and invasion was evaluated using growth curve, MTT assay, wound healing and transwell assay respectively. Results The results demonstrated that TUSC3 mRNA and protein expression levels were down-regulated in CSCC samples. Multivariate and univariate analyses indicated that TUSC3 was an independent prognostic factor for patients with CSCC. Decreased TUSC3 expression levels were significantly associated with proliferation and an aggressive phenotype of cervical cancer cells. Moreover, the knockdown of TUSC3 promoted migration and invasion of cancer cells, while the increased expression of TUSC3 exhibited the opposite effects. The down-regulation of TUSC3 facilitated proliferation and invasion of CSCC cells through the activation of the AKT signaling pathway. Conclusions Our data demonstrated that the down-regulation of TUSC3 promoted CSCC cell metastasis via the AKT signaling pathway. Therefore, TUSC3 may serve as a novel prognostic marker and potential target for CSCC.

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

Bioscience Reports ◽

10.1042/bsr20160447 ◽

2017 ◽

Vol 37 (3) ◽

Cited By ~ 16

Author(s):

Jun Xu ◽

Shouru Zhang ◽

Rong Wang ◽

Xingye Wu ◽

Li Zeng ◽

...

Keyword(s):

Colon Cancer ◽

Protein Expression ◽

Cancer Cells ◽

Signaling Pathway ◽

Akt Signaling ◽

Cancer Resistance ◽

Colon Cancer Cells ◽

Akt Signaling Pathway ◽

Ros Scavenging ◽

Bax Protein

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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