Abstract |
8-Chloro-cyclic AMP (8-Cl-cAMP) is a cyclic AMP analog that induces growth inhibition and apoptosis in a broad spectrum of cancer cells. Previously, we found that 8-Cl-cAMP-induced growth inhibition is mediated by AMP-activated protein kinase (AMPK) as well as p38 mitogen-activated protein kinase ( p38 MAPK). To identify downstream mediators of the 8-Cl-cAMP signaling, we performed co-immunoprecipitation combined with mass spectrometry using the anti-AMPK or p38 MAPK antibodies. Through this approach, SHC1 was identified as one of the binding partners of p38 MAPK. SHC1 phosphorylation was suppressed by 8-Cl-cAMP in HeLa and MCF7 cancer cells, which was mediated by its metabolites, 8-Cl-adenosine and 8-Cl- ATP; however, 8-Cl-cAMP showed no effect on SHC1 phosphorylation in normal human fibroblasts. SHC1 siRNA induced AMPK and p38 MAPK phosphorylation and growth inhibition in cancer cells, and SHC1 overexpression re-sensitized human foreskin fibroblasts to the 8-Cl-cAMP treatment. SHC1 phosphorylation was unaffected by Compound C (an AMPK inhibitor) and SB203580 (a p38 MAPK inhibitor), which suggests that SHC1 is upstream of AMPK and p38 MAPK in the 8-Cl-cAMP-stimulated signaling cascade. On the basis of these findings, we conclude that SHC1 functions as a sensor during the 8-Cl-cAMP-induced growth inhibition in SHC1-overexpressing cancer cells.
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Authors | Ki Young Choi, Young Jun Cho, Jeong Seon Kim, Young-Ho Ahn, Seung Hwan Hong |
Journal | Biochemical and biophysical research communications
(Biochem Biophys Res Commun)
Vol. 463
Issue 4
Pg. 673-8
(Aug 07 2015)
ISSN: 1090-2104 [Electronic] United States |
PMID | 26043699
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2015 Elsevier Inc. All rights reserved. |
Chemical References |
- RNA, Small Interfering
- Shc Signaling Adaptor Proteins
- 8-Bromo Cyclic Adenosine Monophosphate
- 8-chloro-cyclic adenosine monophosphate
- p38 Mitogen-Activated Protein Kinases
- Adenylate Kinase
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Topics |
- 8-Bromo Cyclic Adenosine Monophosphate
(analogs & derivatives, metabolism, pharmacology)
- Adenylate Kinase
(metabolism)
- Cell Division
(drug effects)
- Cell Line, Tumor
- Humans
- Mass Spectrometry
- Neoplasms
(enzymology, pathology, physiopathology)
- Phosphorylation
- RNA, Small Interfering
(genetics)
- Shc Signaling Adaptor Proteins
(genetics, metabolism, physiology)
- Signal Transduction
- p38 Mitogen-Activated Protein Kinases
(metabolism)
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