Angustoline Inhibited Esophageal Tumors Through Regulating LKB1/AMPK/ELAVL1/LPACT2 Pathway and Phospholipid Remodeling

Overview

Journal Front Oncol

Specialty Oncology

Date 2020 Aug 1

PMID 32733803

Citations 3

Authors

Huiying Li

Cheng Zhang

Min Zhang

Qianqian Yao

Huaigu Yang

Linlin Fan

Nan Zheng

Affiliations

Soon will be listed here.

Abstract

Esophageal cancer is a type of gastrointestinal carcinoma and is among the 10 most common causes of cancer death worldwide. However, the specific mechanism and the biomarkers in the proliferation and metastasis of esophageal tumors are still unclear. Therefore, the development of several natural products which could inhibit esophageal tumors deserve attention. In the present study, different sources of cancer cells were used to select the sensitive cell line (esophageal cancer cell KYSE450) and the proper dose of angustoline, which were utilized in the following cell viability, migration and invasion assays. Then the lipidomic detection of clinical samples (tissue and blood plasma) from esophageal cancer patients was performed, to screen out the specific phospholipid metabolites [PC (16:0/18:1) and LPC (16:0)]. Considering lysophosphatidylcholine acyltransferase 2 (LPCAT2) was tightly relative with phospholipids conversion, serine/threonine-protein kinase 11 (LKB1), 5'-monophosphate (AMP)-activated protein kinase (AMPK) and embryonic lethal, and abnormal vision, drosophila-like 1 (ELAVL1) were investigated, to evaluate their expression levels in esophageal tumor tissue and KYSE450 cells. Additionally, KYSE450 tumor bearing mouse model was constructed, the role of angustoline in inhibiting esophageal tumors through regulating LKB1/AMPK/ELAVL1/LPCAT2 pathway was validated, and found that the conversion from LPC (16:0) to PC (16:0/18:1) was blocked by angustoline in some degree. The above results for the first time proved that angustoline suppressed esophageal tumors through activating LKB1/AMPK and inhibiting ELAVL1/LPCAT2, which consequently blocked phospholipid remodeling from LPC (16:0) to PC (16:0/18:1).

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References

Cotte A, Aires V, Ghiringhelli F, Delmas D . LPCAT2 controls chemoresistance in colorectal cancer. Mol Cell Oncol. 2018; 5(3):e1448245. PMC: 6149788. DOI: 10.1080/23723556.2018.1448245. View

Zhuang Z, Di G, Shen Z, Ding J, Shao Z . Enhanced expression of LKB1 in breast cancer cells attenuates angiogenesis, invasion, and metastatic potential. Mol Cancer Res. 2006; 4(11):843-9. DOI: 10.1158/1541-7786.MCR-06-0118. View

Cotte A, Aires V, Fredon M, Limagne E, Derangere V, Thibaudin M . Lysophosphatidylcholine acyltransferase 2-mediated lipid droplet production supports colorectal cancer chemoresistance. Nat Commun. 2018; 9(1):322. PMC: 5778070. DOI: 10.1038/s41467-017-02732-5. View

Liew S, Looi C, Paydar M, Cheah F, Leong K, Wong W . Subditine, a new monoterpenoid indole alkaloid from bark of Nauclea subdita (Korth.) Steud. induces apoptosis in human prostate cancer cells. PLoS One. 2014; 9(2):e87286. PMC: 3925085. DOI: 10.1371/journal.pone.0087286. View

Zhang J, Liu L, Wei S, Gowda G, Hammoud Z, Kesler K . Metabolomics study of esophageal adenocarcinoma. J Thorac Cardiovasc Surg. 2010; 141(2):469-75, 475.e1-4. DOI: 10.1016/j.jtcvs.2010.08.025. View

Liu Q, Chen A, Tang J, Ma Y, Jiang Z, Liu Y . A new indole alkaloid with anti-inflammatory activity from Nauclea officinalis. Nat Prod Res. 2017; 31(18):2107-2112. DOI: 10.1080/14786419.2016.1277351. View

Awwad O, Coperchini F, Pignatti P, Denegri M, Massara S, Croce L . The AMPK-activator AICAR in thyroid cancer: effects on CXCL8 secretion and on CXCL8-induced neoplastic cell migration. J Endocrinol Invest. 2018; 41(11):1275-1282. DOI: 10.1007/s40618-018-0862-8. View

Nishiumi S, Fujigaki S, Kobayashi T, Kojima T, Ito Y, Daiko H . Metabolomics-based Discovery of Serum Biomarkers to Predict the Side-effects of Neoadjuvant Chemoradiotherapy for Esophageal Squamous Cell Carcinoma. Anticancer Res. 2018; 39(1):519-526. DOI: 10.21873/anticanres.13143. View

Zhu X, Wang K, Liu G, Wang Y, Xu J, Liu L . Metabolic Perturbation and Potential Markers in Patients with Esophageal Cancer. Gastroenterol Res Pract. 2017; 2017:5469597. PMC: 5415862. DOI: 10.1155/2017/5469597. View

10.

OBrien A, Villani L, Broadfield L, Houde V, Galic S, Blandino G . Salicylate activates AMPK and synergizes with metformin to reduce the survival of prostate and lung cancer cells ex vivo through inhibition of de novo lipogenesis. Biochem J. 2015; 469(2):177-87. DOI: 10.1042/BJ20150122. View

11.

Morita Y, Sakaguchi T, Ikegami K, Goto-Inoue N, Hayasaka T, Hang V . Lysophosphatidylcholine acyltransferase 1 altered phospholipid composition and regulated hepatoma progression. J Hepatol. 2013; 59(2):292-9. DOI: 10.1016/j.jhep.2013.02.030. View

12.

Zhou J, Huang W, Tao R, Ibaragi S, Lan F, Ido Y . Inactivation of AMPK alters gene expression and promotes growth of prostate cancer cells. Oncogene. 2009; 28(18):1993-2002. PMC: 2679420. DOI: 10.1038/onc.2009.63. View

13.

Abdelzaher E, Mostafa M . Lysophosphatidylcholine acyltransferase 1 (LPCAT1) upregulation in breast carcinoma contributes to tumor progression and predicts early tumor recurrence. Tumour Biol. 2015; 36(7):5473-83. DOI: 10.1007/s13277-015-3214-8. View

14.

Zhang H, Wang L, Hou Z, Ma H, Mamtimin B, Hasim A . Metabolomic profiling reveals potential biomarkers in esophageal cancer progression using liquid chromatography-mass spectrometry platform. Biochem Biophys Res Commun. 2017; 491(1):119-125. DOI: 10.1016/j.bbrc.2017.07.060. View

15.

Zhang X, Chen H, Wang X, Zhao W, Chen J . Expression and transcriptional profiling of the LKB1 tumor suppressor in cervical cancer cells. Gynecol Oncol. 2014; 134(2):372-8. PMC: 4712024. DOI: 10.1016/j.ygyno.2014.04.050. View

16.

Donahue J, Chang E, Xiao L, Wang P, Rao J, Turner D . The RNA-binding protein HuR stabilizes survivin mRNA in human oesophageal epithelial cells. Biochem J. 2011; 437(1):89-96. DOI: 10.1042/BJ20110028. View

17.

Xu X, Song C, Chen Z, Yu C, Wang Y, Tang Y . Downregulation of HuR Inhibits the Progression of Esophageal Cancer through Interleukin-18. Cancer Res Treat. 2017; 50(1):71-87. PMC: 5784622. DOI: 10.4143/crt.2017.013. View

18.

Zhang X, Xu L, Shen J, Cao B, Cheng T, Zhao T . Metabolic signatures of esophageal cancer: NMR-based metabolomics and UHPLC-based focused metabolomics of blood serum. Biochim Biophys Acta. 2013; 1832(8):1207-16. DOI: 10.1016/j.bbadis.2013.03.009. View

19.

Ripley R, Surman D, Diggs L, Trepel J, Lee M, Ryan J . Metabolomic and BH3 profiling of esophageal cancers: novel assessment methods for precision therapy. BMC Gastroenterol. 2018; 18(1):94. PMC: 6013848. DOI: 10.1186/s12876-018-0823-x. View

20.

Grossi V, Lucarelli G, Forte G, Peserico A, Matrone A, Germani A . Loss of STK11 expression is an early event in prostate carcinogenesis and predicts therapeutic response to targeted therapy against MAPK/p38. Autophagy. 2015; 11(11):2102-2113. PMC: 4824604. DOI: 10.1080/15548627.2015.1091910. View