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SHC1 sensitizes cancer cells to the 8-Cl-cAMP treatment.

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.
AuthorsKi Young Choi, Young Jun Cho, Jeong Seon Kim, Young-Ho Ahn, Seung Hwan Hong
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 463 Issue 4 Pg. 673-8 (Aug 07 2015) ISSN: 1090-2104 [Electronic] United States
PMID26043699 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 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
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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