Ursolic acid exerts anti-cancer activity by suppressing vaccinia-related kinase 1-mediated damage repair in lung cancer cells

Kim, Seong Hoon; Ryu, Hye Guk; Lee, Juhyun; Shin, Joon; Harikishore, Amaravadhi; Jung, Hoe‐Yune; Kim, Ye Seul; Lyu, Ha-Na; Oh, Eun-Ji; Baek, Nam‐In; Choi, Kwan-Yong; Yoon, Ho Sup; Kim, Kyong‐Tai

doi:10.1038/srep14570

Cited by 40 publications

(33 citation statements)

References 68 publications

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“…The representatives of the four types of compounds are oleanolic acid, glycyrrhetinic acid, ursolic acid (UA), asiatic acid (AA, 23‐hydroxybetulinic acid), and triptergone (Laszczyk, ; Xiang et al ., ). Among them, UA was frequently reported to have anti‐cancer effects on a variety of malignant tumours, including breast cancer, leukemia, prostate cancer, lung cancer, melanoma, and liver cancer (Novotny et al ., 2001; Shanmugam et al ., ; Shanmugam et al ., ; Kim et al ., ; Kashyap et al ., ; Kim et al ., ; Zhang et al ., ), suggesting its potential application in clinical cancer treatment. There are several underlying anti‐tumour mechanisms for UA, including the activation of c‐Jun N‐terminal kinase (JNK), Ca 2+ release, suppression of NF‐κB, and the signal transduction and activation of transcription‐3 (STAT‐3), and β‐catenin (Shanmugam et al ., ; Kim et al ., ; Kashyap et al ., ; Kim et al ., ; Zhang et al ., ).…”

Section: Introductionmentioning

confidence: 99%

Ursolic acid promotes apoptosis and mediates transcriptional suppression of CT45A2 gene expression in non‐small‐cell lung carcinoma harbouring EGFR T790M mutations

Yang

Chen

Zhou

et al. 2019

British J Pharmacology

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Background and Purpose In non‐small‐cell lung carcinoma (NSCLC) patients, the L858R/T790M mutation of the epithelial growth factor receptor (EGFR) is a major cause of acquired resistance to EGFR‐TKIs treatment that limits their therapeutic efficacy. Identification of drugs that can preferentially kill the NSCLC harbouring L858R/T790M mutation is therefore critical. Here, we have evaluated the effects of ursolic acid, an active component isolated from herbal sources, on erlotinib‐resistant H1975 cells that harbour the L858R/T790M mutation. Experimental Approach Gene expression omnibus (GEO) profiles analyses was applied to detect differentially expressed genes in NSCLC cells harbouring EGFR mutation. AnnexinV‐FITC/PI, TUNEL staining, MTT, wound healing, RT‐PCR, qRT‐PCR, western blots, immunostaining, dual‐luciferase reporters and ChIP‐PCR were utilized to investigate the effects of ursolic acid in vitro and in vivo. Key Results The cancer/testis antigen family 45 member A2 (CT45A2) was highly expressed in H1975 cells. Ectopic expression of CT45A2 in H1975 cells increased cell proliferation and motility in vitro. Silencing the CT45A2 expression strongly attenuated H1975 cells motility and growth. The anti‐cancer effect of ursolic acid was critically dependent on CT45A2 expression in H1975 cells. Ursolic acid suppressed CT45A2 gene transcription mediated by transcriptional factor TCF4 and β‐catenin signalling. Conclusions and Implications CT45A2 is a novel oncogene for NSCLC with an EGFR T790 mutation. Ursolic acid induced apoptosis and inhibited proliferation of H1975 cells by negatively regulating the β‐catenin/TCF4/CT45A2 signalling pathway. Therefore, ursolic acid may be a potential candidate treatment for NSCLC harbouring the EGFR‐L858R/T790M mutation.

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Section: Introductionmentioning

confidence: 99%

Ursolic acid promotes apoptosis and mediates transcriptional suppression of CT45A2 gene expression in non‐small‐cell lung carcinoma harbouring EGFR T790M mutations

Yang

Chen

Zhou

et al. 2019

British J Pharmacology

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“…Recent studies led to the discovery of small molecule VRK1 inhibitors from natural products, such as luteolin, 22 brazilin, 23 and ursolic acid. 24 An extensive thermal shift screening using a well-known kinase library, followed by crystal structure determination, revealed the first molecular basis of the VRK1 inhibitors, ASC24 (PDBID 3OP5), BI-D1870 (PDBID 5UVF), and GW297361X (PDBID 5UKF), providing cues toward possible VRK1 selective inhibitor design. 25 While these inhibitors were shown to recognize the ATP binding pocket, their specificity as ATP-competitive or ATPmimetic VRK1 inhibitors remains elusive.…”

Section: Ngow Et Almentioning

confidence: 99%

Crystal structure of human vaccinia‐related kinase 1 in complex with AMP‐PNP, a non‐hydrolyzable ATP analog

Ngow

Rajan

et al. 2018

Protein Science

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Vaccinia‐related kinase 1 (VRK1), a serine/threonine mitotic kinase, is widely over‐expressed in dividing cells and regarded as a cancer drug target primarily due to its function as an early response gene in cell proliferation. However, the mechanism of VRK1 phosphorylation and substrate activation is not well understood. More importantly even the molecular basis of VRK1 interaction with its cofactor, adenosine triphosphate (ATP), is unavailable to‐date. As designing specific inhibitors remains to be the major challenge in kinase research, such a molecular understanding will enable us to design ATP‐competitive specific inhibitors of VRK1. Here we report the molecular characterization of VRK1 in complex with AMP‐PNP, a non‐hydrolyzable ATP‐analog, using NMR titration followed by the co‐crystal structure determined upto 2.07 Å resolution. We also carried out the structural comparison of the AMP‐PNP bound‐form with its apo and inhibitor‐bound counterparts, which has enabled us to present our rationale toward designing VRK1‐specific inhibitors.

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“…UA exerts anticancer activity in lung cancer cells through inhibition of catalytic activity of Vaccinia-related kinase -1(VRK-1) Cell survival is thus affected. It also blocks VRK-1 induced 53BP1 foci formation and is responsible for improved efficacy during co-administration with DNAdamaging anticancer drugs (Kim et al, 2015). Since, UA is a multi-tasking agent, it can induce death of different cancer cell lines via different mechanisms.…”

Section: Ziziphusmentioning

confidence: 99%

Polyphenols derived from four indigenous Indian fruits for cancer chemoprevention and chemotherapy

Sutapa¹,

Vansh²,

Agarwal³

et al. 2016

J. Med. Plants Res.

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Cancer is one of the major causes of death worldwide, including developing and underdeveloped nations. Mortality and morbidity data suggest that incidences are higher than those of the cardiovascular diseases. High cost and occurrence of numerous side and adverse effects associated with conventional anticancer regimes has necessitated shifting the focus towards the practice of traditional alternative and complementary medicine. Emerging evidence on the beneficial link of dietary components with lower cancer occurrence has been instrumental in determining the course of cancerrelated studies. Consumption of fruits rich in polyphenols has proven to inhibit the process of carcinogenesis and tumor growth, with positive outcomes in terms of survival and quality of life of the patient and thus should be encouraged to combat cancer. The objective of the present review is to highlight the underlying mechanisms of apoptosis induced by the different polyphenolic constituents in four Indian fruits, namely litchi, Indian gooseberry, Indian blackberry and Ziziphus jujube. However, it must be kept in mind that benefits of consuming fruits rich in polyphenols should not be over-judged through food fortification or supplementation with these active principles. Conclusive evidence of the beneficial effects is yet to come through future studies in humans since most of the data have been obtained from in vitro studies.

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Ursolic acid exerts anti-cancer activity by suppressing vaccinia-related kinase 1-mediated damage repair in lung cancer cells

Cited by 40 publications

References 68 publications

Ursolic acid promotes apoptosis and mediates transcriptional suppression of CT45A2 gene expression in non‐small‐cell lung carcinoma harbouring EGFR T790M mutations

Ursolic acid promotes apoptosis and mediates transcriptional suppression of CT45A2 gene expression in non‐small‐cell lung carcinoma harbouring EGFR T790M mutations

Crystal structure of human vaccinia‐related kinase 1 in complex with AMP‐PNP, a non‐hydrolyzable ATP analog

Polyphenols derived from four indigenous Indian fruits for cancer chemoprevention and chemotherapy

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