¹Department of Medicine, Division of Hematology/Oncology, Northwestern University Medical School and the Robert H Lurie Cancer Center of Northwestern University, Chicago, IL, USA

Correspondence: Dr RC Bergan, Division of Hematology/Oncology, Department of Medicine, Northwestern University Medical School, McGaw no. 2301, 240 East Huron St., Chicago, IL, USA. E-mail: r-bergan@northwestern.edu

Received 13 June 2005; Revised 15 November 2005; Accepted 19 November 2005; Published online 16 January 2006.

Abstract

Although cell invasion is a necessary early step in cancer metastasis, its regulation is not well understood. We have previously shown, in human prostate cancer, that transforming growth factor (TGF)-mediated increases in cell invasion are dependent upon activation of the serine/threonine kinase, p38 MAP kinase. In the current study, downstream effectors of p38 MAP kinase were sought by first screening for proteins phosphorylated after TGF treatment, only in the absence of chemical inhibitors of p38 MAP kinase. This led us to investigate mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2), a known substrate of p38 MAP kinase, as well as heat-shock protein 27 (HSP27), a known substrate of MAPKAPK2, in both PC3 and PC3-M human prostate cells. After transient transfection, wild-type MAPKAPK2 and HSP27 both increased TGF-mediated matrix metalloproteinase type 2 (MMP-2) activity, as well as cell invasion, which in turn was inhibited by SB203580, an inhibitor of p38 MAP kinase. Conversely, dominant-negative MAPKAPK2 blocked phosphorylation of HSP27, whereas dominant-negative MAPKAPK2 or mutant, non-phosphorylateable, HSP27 each blocked TGF-mediated increases in MMP-2, as well as cell invasion. Similarly, knock down of MAPKAPK2, HSP27 or both together, by siRNA, also blocked TGF-mediated cell invasion. This study demonstrates that both MAPKAPK2 and HSP27 are necessary for TGF-mediated increases in MMP-2 and cell invasion in human prostate cancer.