Trifluoperazine Activates FOXO1-Related Signals to Inhibit Tumor Growth in Hepatocellular Carcinoma

Jiang, Jingwen; Huang, Zhong-Xi; Chen, Xuewu; Luo, Rong; Cai, Hongbin; Wang, Hairu; Zhang, Hui; Sun, Tao; Zhang, Yunfang

doi:10.1089/dna.2017.3790

Cited by 29 publications

(25 citation statements)

References 26 publications

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“…TFP is a promising anticancer candidate which has been extensively investigated. It has been shown to suppress several types of cancer, including breast cancer, lung cancer, hepatocellular carcinoma, and glioblastoma (Chi-Tai et al, 2012; Park et al, 2016; Jiang et al, 2017; Kang et al, 2017). Drug resistance and metastasis to other organs of the body are the two major obstacles to successful cancer treatment (Cao et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…TFP has been shown to induce G0/G1 cell cycle arrest in several studies (Jiang et al, 2017; Wang et al, 2017; Feng et al, 2018). An uncontrolled, abnormal cell cycle is one hallmark of cancer (Hanahan and Weinberg, 2011), and many proteins are involved in cell cycle regulation.…”

Section: Discussionmentioning

confidence: 99%

“…TFP is also shown to promote FOXO3 nuclear localization and activation to suppress breast cancer (Park et al, 2016). In hepatocellular carcinoma, TFP could activate forkhead box O1 (FOXO1)–related signals to inhibit tumor growth (Jiang et al, 2017). The receptor tyrosine kinase AXL is another target of TFP to reduce growth and metastasis of breast cancer (Goyette et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and Apoptosis

et al. 2019

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Repurposing existing drugs for cancer treatment is an effective strategy. An approved antipsychotic drug, trifluoperazine (TFP), has been reported to have potential anticancer effects against several cancer types. Here, we investigated the effect and molecular mechanism of TFP in colorectal cancer (CRC). In vitro studies showed that TFP induced G0/G1 cell cycle arrest to dramatically inhibit CRC cell proliferation through downregulating cyclin-dependent kinase (CDK) 2, CDK4, cyclin D1, and cyclin E and upregulating p27. TFP also induced apoptosis, decreased mitochondrial membrane potential, and increased reactive oxygen species levels in CRC cells, indicating that TFP induced mitochondria-mediated intrinsic apoptosis. Importantly, TFP significantly suppressed tumor growth in two CRC subcutaneous tumor models without side effects. Interestingly, TFP treatment increased the expression levels of programmed death-1 ligand 1 (PD-L1) in CRC cells and programmed death-1 (PD-1) in tumor-infiltrating CD4+ and CD8+ T cells, implying that the combination of TFP with an immune checkpoint inhibitor, such as an anti-PD-L1 or anti-PD-1 antibody, might have synergistic anticancer effects. Taken together, our study signifies that TFP is a novel treatment strategy for CRC and indicates the potential for using the combination treatment of TFP and immune checkpoint blockade to increase antitumor efficiency.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and Apoptosis

et al. 2019

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“…FOXO1 was considered a tumor suppressor gene in HCC, which was reported to reverse epithelial-interstitial transformation by inhibiting invasion and metastasis of HCC cells [13]. Jiang et al [14] researched that some drugs (such as Trifluoperazine) might inhibit HCC growth via activating FOXO1. In HCC, FOXO1 has also been found to be regulated by several miRNAs.…”

Section: Introductionmentioning

confidence: 99%

miR-96 exerts carcinogenic effect by activating AKT/GSK-3β/β-catenin signaling pathway through targeting inhibition of FOXO1 in hepatocellular carcinoma

et al. 2019

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Background The aim of this research was to investigate the mechanism of miR-96 affecting hepatocellular carcinoma (HCC). Methods mRNA and protein expression was detected by qRT-PCR and Western blot, respectively. HepG2 cells were transfected and grouped as follows: miR-NC group, miR-mimics group, NC + Vector group, mimics + Vector group, mimics + FOXO1 group. Luciferase reporter assay was performed. MTT and Transwell assay was conducted. In vivo studies by nude mice were performed. Immunohistochemistry and immunofluorescence was executed. Results Up-regulated miR-96 and down-regulated FOXO1 was found in tumor tissues and HepG2 cells ( P < 0.01). FOXO1 was directly suppressed by miR-96. Compared with NC + Vector group, mimics + Vector group has higher OD495 value ( P < 0.05), higher migration and invasion cells ( P < 0.01), larger transplanted tumor volume ( P < 0.01), lower FOXO1 positive cell numbers ( P < 0.01), higher p-AKT and p-GSK-3β expression ( P < 0.01), lower p-β-catenin expression ( P < 0.01), more β-catenin expression in the nucleus ( P < 0.01). Compared with mimics + Vector group, mimics + FOXO1 group has lower OD495 value ( P < 0.05), lower migration and invasion cells (P < 0.01), smaller transplanted tumor volume ( P < 0.01), higher FOXO1 positive cells ( P < 0.01), lower p-AKT and p-GSK-3β expression ( P < 0.01), higher p-β-catenin expression ( P < 0.01), less β-catenin expression in the nucleus ( P < 0.01). Conclusion miR-96 exerts carcinogenic effect by activating AKT/GSK-3β/β-catenin signaling pathway through targeting inhibition of FOXO1 in HCC.

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“…TFP has shown in vivo anticancer activity in glioblastoma [3], colorectal cancer [4], and triple-negative breast cancer [5], among others. Subsequently, several studies have demonstrated that TFP can inhibit cell migration and proliferation, promote cell cycle arrest, induce apoptosis, and inhibit autophagy in multiple cancer cell lines [6,7]. Recently, we found that TFP binds and mimics the effect of the genetic inhibition of NUPR1, a stress protein that promotes tumor growth and acts as a strong anticancer drug in vitro and in vivo in xenografted nude mice [8].…”

Section: Introductionmentioning

confidence: 99%

Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma

Huang

Lan

Fraunhoffer

et al. 2019

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with almost no curative chemotherapeutic treatment. Besides the development of new compounds, repurposing of approved drugs to treat cancer, alone or in combination, has become an attractive strategy, showing many therapeutic and economic advantages. However, it is necessary to improve our knowledge about the mechanism of cell death elicited by approved drugs itself, but also to rationally develop more powerful multidrug treatments. In this work, we focus our attention on determining the mechanism promoting cell death following trifluoperazine (TFP) treatment, which is an antipsychotic drug with strong anticancer activity in PDAC. We demonstrate that TFP induces cell death by apoptosis and necroptosis, which can be partially inhibited by Z-VAD-FMK as well as necrostatin-1, respectively. This cell death promotion is triggered by a poor ATP content, observed in TFP-treated cells as a consequence of a dramatic decrease in OXPHOS metabolism due to mitochondrial stress. Remarkably, mitochondrial homeostasis was seriously affected, and a loss of mitochondrial membrane potential and ROS overproduction was observed. Moreover, this mitochondrial stress was coupled with an ER stress and the activation of the endoplasmic-reticulum-associated protein degradation (ERAD) and the unf olded protein response (UPR) pathways. We took advantage of this information and inhibited this process by using the proteasome inhibitors MG-132 or bortezomib compounds in combination with TFP and found a significant improvement of the anticancer effect of the TFP on primary PDAC-derived cells. In conclusion, this study not only uncovers the molecular mechanisms that are triggered upon TFP-treatment but also its possible combination with bortezomib for the future development of therapies for pancreatic cancer.

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Trifluoperazine Activates FOXO1-Related Signals to Inhibit Tumor Growth in Hepatocellular Carcinoma

Cited by 29 publications

References 26 publications

Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and Apoptosis

Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and Apoptosis

miR-96 exerts carcinogenic effect by activating AKT/GSK-3β/β-catenin signaling pathway through targeting inhibition of FOXO1 in hepatocellular carcinoma

Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma

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