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Aldo-keto reductase 1B10 (AKR1B10) is upregulated in breast cancer and promotes tumor growth and metastasis. However, little is known of the molecular mechanisms of action. Herein we report that AKR1B10 activates lipid second messengers to stimulate cell proliferation. Our data showed that ectopic expression of AKR1B10 in breast cancer cells MCF-7 promoted lipogenesis and enhanced levels of lipid second messengers, including phosphatidylinositol bisphosphate (PIP2), diacylglycerol (DAG), and inositol triphosphate (IP3). In contrast, silencing of AKR1B10 in breast cancer cells BT-20 and colon cancer cells HCT-8 led to decrease of these lipid messengers. Qualitative analyses by liquid chromatography-mass spectrum (LC-MS) revealed that AKR1B10 regulated the cellular levels of total DAG and majority of subspecies. This in turn modulated the phosphorylation of protein kinase C (PKC) isoforms PKCδ (Thr505), PKCµ (Ser744/748), and PKCα/βII (Thr638/641) and activity of the PKC-mediated c-Raf/MEK/ERK signaling cascade. A pan inhibitor of PKC (Go6983) blocked ERK1/2 activation by AKR1B10. In these cells, phospho-p90RSK, phospho-MSK, and Cyclin D1 expression was increased by AKR1B10, and pharmacological inhibition of the ERK signaling cascade with MEK1/2 inhibitors U0126 and PD98059 eradicated induction of phospho-p90RSK, phospho-MSK, and Cyclin D1. In breast cancer cells, AKR1B10 promoted the clonogenic growth and proliferation of breast cancer cells in two-dimension (2D) and three-dimension (3D) cultures and tumor growth in immunodeficient female nude mice through activation of the PKC/ERK pathway. These data suggest that AKR1B10 stimulates breast cancer cell growth and proliferation through activation of DAG-mediated PKC/ERK signaling pathway.

Titel:	AKR1B10 activates diacylglycerol (DAG) second messenger in breast cancer cells.
Autor/in / Beteiligte Person:	Huang, C ; Cao, Z ; Ma, J ; Shen, Y ; Bu, Y ; Khoshaba, R ; Shi, G ; Huang, D ; Liao, DF ; Ji, H ; Jin, J ; Cao, D
Link:	Full Text Finder (Volltext)
Zeitschrift:	Molecular carcinogenesis, Jg. 57 (2018-10-01), Heft 10, S. 1300-1310
Veröffentlichung:	<2005- > : [Hoboken, N.J.] : Wiley-Liss ; <i>Original Publication</i>: New York : Alan R. Liss, Inc., c1988-, 2018
Medientyp:	academicJournal
ISSN:	1098-2744 (electronic)
DOI:	10.1002/mc.22844
Schlagwort:	Aldo-Keto Reductase Family 1 member B10 genetics Animals Breast Neoplasms genetics Breast Neoplasms pathology Cell Line, Tumor Female HEK293 Cells Humans Lipogenesis MAP Kinase Signaling System MCF-7 Cells Mice, Nude Protein Kinase C metabolism Transplantation, Heterologous Tumor Burden Aldo-Keto Reductase Family 1 member B10 metabolism Breast Neoplasms metabolism Diglycerides metabolism Second Messenger Systems
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Mol Carcinog] 2018 Oct; Vol. 57 (10), pp. 1300-1310. <i>Date of Electronic Publication: </i>2018 Jun 28. MeSH Terms: Second Messenger Systems* ; Aldo-Keto Reductase Family 1 member B10 / metabolism ; Breast Neoplasms / metabolism ; Diglycerides / *metabolism ; Aldo-Keto Reductase Family 1 member B10 / genetics ; Animals ; Breast Neoplasms / genetics ; Breast Neoplasms / pathology ; Cell Line, Tumor ; Female ; HEK293 Cells ; Humans ; Lipogenesis ; MAP Kinase Signaling System ; MCF-7 Cells ; Mice, Nude ; Protein Kinase C / metabolism ; Transplantation, Heterologous ; Tumor Burden References: Chem Biol Interact. 2009 Mar 16;178(1-3):171-7. (PMID: 19014918) ; Nat Rev Cancer. 2007 Apr;7(4):281-94. (PMID: 17384583) ; Int J Cancer. 2007 Nov 15;121(10):2301-6. (PMID: 17597105) ; Biochem J. 2012 Mar 1;442(2):273-82. (PMID: 22329800) ; Toxicol Sci. 2007 Jun;97(2):562-8. (PMID: 17329238) ; Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20764-9. (PMID: 18087047) ; Oncogene. 1999 May 20;18(20):3085-97. (PMID: 10340380) ; Nat Rev Mol Cell Biol. 2008 Feb;9(2):112-24. (PMID: 18216768) ; J Lipid Res. 1989 May;30(5):761-4. (PMID: 2760549) ; Clin Cancer Res. 2005 Mar 1;11(5):1776-85. (PMID: 15755999) ; Cell Metab. 2013 Aug 6;18(2):153-61. (PMID: 23791484) ; Methods. 2003 Jul;30(3):256-68. (PMID: 12798140) ; J Biol Chem. 2008 Feb 8;283(6):3418-23. (PMID: 18056116) ; Biochem J. 2007 Jul 1;405(1):95-105. (PMID: 17381426) ; Oxid Med Cell Longev. 2016;2016:9875298. (PMID: 26823956) ; Chem Biol Interact. 2011 May 30;191(1-3):192-8. (PMID: 21329684) ; Int J Cancer. 2000 Apr 15;86(2):169-73. (PMID: 10738242) ; Gan. 1982 Oct;73(5):681-3. (PMID: 6762317) ; Mol Cancer Res. 2010 Mar;8(3):421-32. (PMID: 20197379) ; Int J Cancer. 2012 Sep 15;131(6):E862-71. (PMID: 22539036) ; Clin Cancer Res. 2015 Mar 15;21(6):1466-76. (PMID: 25538260) ; J Biol Chem. 2009 Sep 25;284(39):26742-8. (PMID: 19643728) ; Cancer Lett. 2006 Apr 8;235(1):1-10. (PMID: 15907369) ; Curr Opin Clin Nutr Metab Care. 2006 Jul;9(4):358-65. (PMID: 16778563) ; Nat Rev Cancer. 2007 Oct;7(10):763-77. (PMID: 17882277) ; Biochem J. 2011 Aug 15;438(1):71-80. (PMID: 21585341) ; Mol Carcinog. 2017 Jan;56(1):118-129. (PMID: 26969882) ; Cell Res. 2002 Mar;12(1):9-18. (PMID: 11942415) ; FEBS J. 2012 Aug;279(15):2610-23. (PMID: 22621751) ; Mod Pathol. 2012 May;25(5):758-66. (PMID: 22222635) ; Nat Cell Biol. 2015 Apr;17(4):351-9. (PMID: 25774832) ; Toxicol Appl Pharmacol. 2011 Aug 15;255(1):40-7. (PMID: 21640744) ; Biochem Biophys Res Commun. 2009 Sep 18;387(2):245-50. (PMID: 19563777) ; Pflugers Arch. 2005 May;450(2):75-82. (PMID: 15614575) ; J Biol Chem. 1998 May 8;273(19):11429-35. (PMID: 9565553) ; J Recept Signal Transduct Res. 2015;35(6):600-4. (PMID: 26096166) ; Front Physiol. 2015 Dec 16;6:382. (PMID: 26733270) ; Drug Metab Dispos. 2006 Mar;34(3):464-70. (PMID: 16381663) ; Curr Opin Cell Biol. 1996 Apr;8(2):159-67. (PMID: 8791422) ; Oncotarget. 2016 Jul 12;7(28):43779-43791. (PMID: 27248472) ; Arch Toxicol. 2000 Sep;74(7):404-14. (PMID: 11043496) Grant Information: P30 CA076292 United States CA NCI NIH HHS; P30 DK020579 United States DK NIDDK NIH HHS Contributed Indexing: Keywords: AKR1B10; PKC/ERK cascade; breast cancer; diacylglycerol; lipid second messengers; phosphatidylinositol bisphosphate Substance Nomenclature: 0 (Diglycerides) ; EC 1.1.1.- (Aldo-Keto Reductase Family 1 member B10) ; EC 2.7.11.13 (Protein Kinase C) Entry Date(s): Date Created: 20180531 Date Completed: 20190503 Latest Revision: 20201130 Update Code: 20231215 PubMed Central ID: PMC6800193

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AKR1B10 activates diacylglycerol (DAG) second messenger in breast cancer cells.