HSP90 and HSP70 proteins are essential for stabilization and activation of WASF3 metastasis-promoting protein.
Inactivation of HSP90 and HSP70 leads to loss of invasion in a variety of cancer cell types, presumably as a result of destabilization of, as yet, undefined clients of these molecular chaperones that influence this phenotype. The WASF3 gene has been shown to be up-regulated in high-grade tumors and its down-regulation leads to loss of invasion and metastasis. WASF3 phosphorylation by ABL kinase is essential for its ability to regulate invasion. Mass spectroscopy analysis now shows that HSP90 is present in the WASF3 immunocomplex from prostate cancer cells. Inactivation of HSP90 in these and other cell types does not affect WASF3 stability but prevents its phosphoactivation as a result of destabilization of ABL. HSP70 was also found in the WASF3 immunocomplex and inactivation of HSP70 results in destabilization of WASF3 through proteasome degradation. Knockdown of WASF3, HSP90, and HSP70 individually, all lead to loss of invasion but as knockdown of WASF3 in the presence of robust expression of HSP90/70 has the same effect, it seems that the influence these chaperone proteins have on invasion is mediated, at least in part, by their control over the critical invasion promoting capacity of the WASF3 protein. Overexpression of HSP70 in WASF3 null cells does not enhance invasion. These observations suggest that targeting HSP90/70 may have efficacy in reducing cancer cell invasion.
Georgia Health Sciences University Cancer Center, Augusta, Georgia 30912.
Yong
Y
Teng
Georgia Health Sciences University Cancer Center, Augusta, Georgia 30912.
Lambert
L
Ngoka
Georgia Health Sciences University Cancer Center, Augusta, Georgia 30912.
Yun
Y
Mei
Georgia Health Sciences University Cancer Center, Augusta, Georgia 30912.
Leslieann
L
Lesoon
Georgia Health Sciences University Cancer Center, Augusta, Georgia 30912. Electronic address: jcowell@georgiahealth.edu.
John K
JK
Cowell
D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D055550:Protein Stability; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000235:genetics / Q000378:metabolism*
D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; C120153:WASF3 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; D016315:Proto-Oncogene Proteins c-abl