Mirk/dyrk1B kinase is upregulated following inhibition of mTOR.

Abstract

The PI3K/PTEN/Akt/mTOR/p70S6K pathway is one of the most frequently deregulated signaling pathways in solid tumors and has a functional role in drug resistance. However, targeting this pathway leads to compensatory activation of several mediators of cell survival. Expression of the reactive oxygen species-controlling kinase Mirk/dyrk1B was increased severalfold by the mammalian target of rapamycin (mTOR) inhibitors RAD001, WYE354 and rapamycin, with less effect by the Akt inhibitors AZD5363 and MK-2206. Upregulation of Mirk messenger RNA (mRNA) expression was mediated by cyclic AMP response element binding protein (CREB) binding to two sites in the Mirk promoter upstream of the transcription start site and one site within exon 4. Depletion of CREB reduced Mirk expression, whereas depletion of mTOR increased it. Moreover, hydroxytamoxifen activation of an Akt-estrogen receptor construct blocked an increase in Mirk mRNA and protein. Addition of a Mirk/dyrk1B kinase inhibitor increased the sensitivity of Panc1 pancreatic cancer cells and three different ovarian cancer cell lines to the mTOR inhibitor RAD001. Targeting Mirk kinase could improve the utility of mTOR inhibitors and so presents an attractive drug target.

• Authors: Xiaobing Deng, Jing Hu, Daina Z Ewton, Eileen Friedman
• Journal: Carcinogenesis (Carcinogenesis) Vol. 35 Issue 9 Pg. 1968-76 (Sep 2014) ISSN: 1460-2180 [Electronic] England
• PMID: 24590896 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press.

Chemical References

• CREB1 protein, human
• Chromones
• Cyclic AMP Response Element-Binding Protein
• Morpholines
• RNA, Messenger
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Everolimus
• Dyrk kinase
• MTOR protein, human
• Protein-Tyrosine Kinases
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Cell Line, Tumor
• Chromones (pharmacology)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Drug Synergism
• Enzyme Activation
• Everolimus
• Gene Expression
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Morpholines (pharmacology)
• Promoter Regions, Genetic
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Messenger (genetics, metabolism)
• Signal Transduction
• Sirolimus (analogs & derivatives, pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Up-Regulation (drug effects)