title: 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.
authors.affiliation: School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Ki Young
authors.initials: KY
authors.lastname: Choi
authors.affiliation: School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Cho
authors.affiliation: Department of Molecular Medicine, Ewha Womans University School of Medicine, Seoul 158-710, Republic of Korea.
authors.forename: Jeong Seon
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine, Ewha Womans University School of Medicine, Seoul 158-710, Republic of Korea. Electronic address: yahn@ewha.ac.kr.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Ahn
authors.affiliation: School of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address: shong100@snu.ac.kr.
authors.forename: Seung Hwan
authors.initials: SH
authors.lastname: Hong
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000263:Adenylate Kinase / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D013058:Mass Spectrometry; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D055765:Shc Signaling Adaptor Proteins; D015124:8-Bromo Cyclic Adenosine Monophosphate; C044258:8-chloro-cyclic adenosine monophosphate; D048051:p38 Mitogen-Activated Protein Kinases; D000263:Adenylate Kinase
keywords: 8-Chloro-cyclic AMP; AMP-activated protein kinase; Cancer therapy; SHC1; p38 MAP kinase