Anti-allergic drug azelastine suppresses colon tumorigenesis by directly targeting ARF1 to inhibit IQGAP1-ERK-Drp1-mediated mitochondrial fission

Hu, Huifang; Xu, Wen; Li, Yang-Jia; He, Yan; Zhang, Wei-Xia; Liao, Long; Zhang, Qihua; Liang, Han; Yin, Xinhua; Zhao, Xiangxuan; Pan, Yun-long; Li, Bin; He, Qing‐Yu

doi:10.7150/thno.48698

Cited by 40 publications

(51 citation statements)

References 43 publications

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“…Cholesterol metabolism has been proven to promote the survival and drug resistance of tumor cells to a certain extent ( Silvente-Poirot and Poirot, 2014 ; Yan et al, 2020 ). We have confirmed that the AKT/ERK pathway participates in the growth and metastasis of cancer cells in our previous studies, and this pathway has been proven to be the target of many anticancer drugs ( Xu et al, 2018 ; Hong et al, 2020 ; Xu et al, 2020 ; Hu et al, 2021 ). An increasing number of studies have confirmed that SREBP2 indeed plays a cancer-promoting role by regulating cholesterol metabolism in HCC ( Yang et al, 2019 ; Che et al, 2020 ; Liu et al, 2020 ), and SREBP2 has been proven to be the target of some anticancer drugs ( Kim et al, 2018 ; Kim et al, 2019 ).…”

Section: Introductionsupporting

confidence: 85%

Maprotiline Suppresses Cholesterol Biosynthesis and Hepatocellular Carcinoma Progression Through Direct Targeting of CRABP1

Zheng

Zhu²,

Liu³

et al. 2021

Front. Pharmacol.

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Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related death and has a poor prognosis worldwide, thus, more effective drugs are urgently needed. In this article, a small molecule drug library composed of 1,056 approved medicines from the FDA was used to screen for anticancer drugs. The tetracyclic compound maprotiline, a highly selective noradrenergic reuptake blocker, has strong antidepressant efficacy. However, the anticancer effect of maprotiline remains unclear. Here, we investigated the anticancer potential of maprotiline in the HCC cell lines Huh7 and HepG2. We found that maprotiline not only significantly restrained cell proliferation, colony formation and metastasis in vitro but also exerted antitumor effects in vivo. In addition to the antitumor effect alone, maprotiline could also enhance the sensitivity of HCC cells to sorafenib. The depth studies revealed that maprotiline substantially decreased the phosphorylation of sterol regulatory element-binding protein 2 (SREBP2) through the ERK signaling pathway, which resulted in decreased cholesterol biosynthesis and eventually impeded HCC cell growth. Furthermore, we identified cellular retinoic acid binding protein 1 (CRABP1) as a direct target of maprotiline. In conclusion, our study provided the first evidence showing that maprotiline could attenuate cholesterol biosynthesis to inhibit the proliferation and metastasis of HCC cells through the ERK-SREBP2 signaling pathway by directly binding to CRABP1, which supports the strategy of repurposing maprotiline in the treatment of HCC.

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Section: Introductionsupporting

confidence: 85%

Maprotiline Suppresses Cholesterol Biosynthesis and Hepatocellular Carcinoma Progression Through Direct Targeting of CRABP1

Zheng

Zhu²,

Liu³

et al. 2021

Front. Pharmacol.

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“…A novel use of aspirin against prostate cancer has also been reported [46] . Our previous studies also identi ed several traditional drugs that exhibit potential anticancer actions [15,22,24,47,48] . In the present study, lomitapide, an inhibitor of MTP routinely applied in the management of hypercholesterolemia, was found to suppress CRC growth through activation of autophagy, further implying the signi cance of drug repurposing in the development of cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Quantitative proteomic analysis coupled with bioinformatics analysis has been identi ed as a favorable strategy for exploring the molecular mechanism underlying the actions of small molecules [14] . In previous studies, we successfully used drug a nity responsive target stability (DARTS) technology to demonstrate that ADP-ribosylation factor 1 (ARF1) acts as a direct target and mediates the anticancer effect of azelastine [15] . In contrast to DARTS technology, the optimized limited proteolysis-mass spectrometry (LiP-SMap) method takes advantage of high-resolution LC-MS/MS and high-throughput quantitative proteomic technology to identify increased peptide levels upon limited proteolysis.…”

Section: Introductionmentioning

confidence: 99%

Targeting PP2A with lomitapide suppresses colorectal tumorigenesis through the activation of AMPK/Beclin1-mediated autophagy

et al. 2021

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BackgroundColorectal cancer (CRC) is one of the most malignant cancer worldwide, and the limited e cacy of existing treatments is the leading cause of death in patients with CRC. Thus, novel drugs for CRC treatment are urgently needed. MethodsWe screened an FDA-approved small-molecule library upon HCT116 cells, and identi ed lomitapide as a novel CRC anticancer compound. Then we con rmed the activities of lomitapide on CRC cells by WST-1 assay, colony formation, and ow cytometry. RNA sequencing and GO analysis were used to investigate

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“…Increasing amounts of tumor biomarkers have been discovered by quantitative proteomics. 57 , 58 , 59 Samples from tumor tissue and paired adjacent tissue or patients and healthy people were prepared, digested into peptides, and then analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). After quantification and filtration, tumor biomarkers were identified ( Figure 4 ).…”

Section: Identifying Potential Biomarkers With Quantitative Proteomicsmentioning

confidence: 99%

“…Quantitative proteomics is a promising tool for revealing the molecular mechanisms of drug action. 58 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 Proteomics drug maps have greatly promoted the discovery of drug targets. After the quantitative analysis for 10,000 proteins and 55,000 phosphorylation sites (p-sites) from 125 cancer cell lines, the proteome activity landscapes were obtained.…”

Section: Discovering Drug Targets With Quantitative Proteomicsmentioning

confidence: 99%

Quantitative proteomics characterization of cancer biomarkers and treatment

Yang

Shi

Zhang

et al. 2021

Molecular Therapy - Oncolytics

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Cancer accounted for 16% of all death worldwide in 2018. Significant progress has been made in understanding tumor occurrence, progression, diagnosis, treatment, and prognosis at the molecular level. However, genomics changes cannot truly reflect the state of protein activity in the body due to the poor correlation between genes and proteins. Quantitative proteomics, capable of quantifying the relatively different protein abundance in cancer patients, has been increasingly adopted in cancer research. Quantitative proteomics has great application potentials, including cancer diagnosis, personalized therapeutic drug selection, real-time therapeutic effects and toxicity evaluation, prognosis and drug resistance evaluation, and new therapeutic target discovery. In this review, the development, testing samples, and detection methods of quantitative proteomics are introduced. The biomarkers identified by quantitative proteomics for clinical diagnosis, prognosis, and drug resistance are reviewed. The challenges and prospects of quantitative proteomics for personalized medicine are also discussed.

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Anti-allergic drug azelastine suppresses colon tumorigenesis by directly targeting ARF1 to inhibit IQGAP1-ERK-Drp1-mediated mitochondrial fission

Cited by 40 publications

References 43 publications

Maprotiline Suppresses Cholesterol Biosynthesis and Hepatocellular Carcinoma Progression Through Direct Targeting of CRABP1

Maprotiline Suppresses Cholesterol Biosynthesis and Hepatocellular Carcinoma Progression Through Direct Targeting of CRABP1

Targeting PP2A with lomitapide suppresses colorectal tumorigenesis through the activation of AMPK/Beclin1-mediated autophagy

Quantitative proteomics characterization of cancer biomarkers and treatment

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