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HSP90 is a Novel Target of Thrombospondin‐1 to Regulate Colon Cancer Development
Author(s) -
Ling Jun,
Gutierrez Linda,
Lopez-Dee Zenaida,
Pan Songqin,
Kalter Valarie,
Cottell Colby,
Nye Derek
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.615.10
Subject(s) - thrombospondin 1 , hsp90 , kinase , cancer research , hsp90 inhibitor , chemistry , immunoprecipitation , angiogenesis , biology , biochemistry , heat shock protein , gene
Thrombospondin‐1 (TSP‐1) is the first identified endogenous inhibitor of angiogenesis; it has been demonstrated to regulate colon cancer development in a colitis‐associated mouse model. Here, we reported for the first time that TSP‐1 down‐regulated the expression of HSP90α. TSP‐1 knock‐out mice (TSP‐1 −/− ) showed no difference at HSP90α level with wild type (WT) mice under normal and mild inflamed conditions, but expressed elevated HSP90α at inflamed stage induced by DSS/AOM and a complicated pattern of HSP90α degradation at cancerous lesion stage. The over‐expression of HSP90α in TSP‐1 −/− mice under these conditions was confirmed by mass spectrometry, real‐time RT‐PCR and immunohistochemical staining. The transient overexpression of TSP‐1 in HEK 293 cells down‐regulated the level of HSP90α, confirming the casual relationship of TSP‐1 with HSP90α. To search for kinases downstream TSP‐1 signaling, Erk2 was identified to be sensitive to TSP‐1 activation, thereby inhibition of Erk2 activity by kinase inhibitor enhanced the level of HSP90α, defining Erk2 as one of effector kinases to regulate the expression or stability HSP90α by TSP‐1. Co‐immunoprecipitation revealed that HSP90α interacted with TSP‐1, thus providing another mechanism that TSP‐1 might regulate HSP90α at protein‐protein interaction level. In sum, we identified a novel mechanism of TSP‐1 function via HSP90α in colon cancer progression.