HSP27 is required for invasion and metastasis triggered by hepatocyte growth factor

Abstract

The hepatocyte growth factor (HGF) also known as scatter factor activates cancer cell invasion and metastasis. We show that in ovarian cancer cells HGF induced the phosphorylation of the small heat shock protein of 27 kDa (HSP27) by activating the p38MAPK. HSP27 is increased in many cancers at advanced stage including ovarian cancer and associated with cancer resistance to therapy and poor patients' survival. The phosphorylation of HSP27 regulates both its chaperone activity and its control of cytoskeletal stability. We show that HSP27 was necessary for the remodeling of actin filaments induced by HGF and that motility in vitro depended on the p38MAPK-MK2 axis. In vivo, HSP27 silencing impaired the ability of the highly metastatic, HGF-secreting ovarian cancer cells to give rise to spontaneous metastases. This was due to defective motility across the vessel wall and reduced growth. Indeed, HSP27 silencing impaired the ability of circulating ovarian cancer cells to home to the lungs and to form experimental hematogenous metastases and the capability of cancer cells to grow as subcutaneous xenografts. Moreover, HSP27 suppression resulted in the sensitization of xenografts to low doses of the chemotherapeutic paclitaxel, likely because HSP27 protected microtubules from bundling caused by the drug. Altogether, these data show that the HSP27 is required for the proinvasive and prometastatic activity of HGF and suggest that HSP27 might be not only a marker of progression of ovarian cancer, but also a suitable target for therapy.

Heat Shock Proteins Promote Cancer: It's a Protection Racket

“…MET appears to be an important client for HSPs in cancer and Hsp70 inactivation leads to decreased MET expression and loss of MET autophosphorylation in mammary tumors [36, 66]. Hsp27 expression also favors metastasis though its effects on a process known as the epithelial-mesenchymal transition, in which cells switch from a compact shape to a spindle shape and gain enhanced cell motility [67–69]. In addition, elevated co-chaperone levels also promote (prostate) cancer; increased levels of the Hsp90 co-chaperone p23 increases metastasis in prostate cancer[70].…”

Heat Shock Protein 27 (HSP27, HSPB1) Is Up-Regulated by Targeted Agents and Confers Resistance to Both Targeted Drugs and Chemotherapeutics

“…2.3a). In vivo, it was shown that HSP27 suppression resulted in the sensitization of xenografts to low doses of PTX [17]. This was expected also because HSP27 protects microtubules from bundling caused by the drug [17].…”

“…This was due to defective motility across the vessel wall and reduced growth. Indeed, HSP27 silencing impaired the ability of circulating ovarian cancer cells to home to the lungs and to form experimental haematogenous metastases and the capability of cancer cells to grow as subcutaneous xenografts [17]. Altogether, these data showed that HSP27 is required for the pro-invasive and pro-metastatic activity of HGF and suggest that HSP27 might be not only a marker of progression of ovarian cancer, but also a suitable target for therapy.…”

HSP27 as a Therapeutic Target of Novel Inhibitors and Dietary Phytochemicals in Cancer

“…Many studies showed that high expression of HSP27 in cancer has been associated with metastasis [31][32][33] and has been described as differential prognostic marker [34][35][36]. HSP27 studies in animal models shown increased tumourigenic potential of rodent cells transplanted in syngeneic hosts [33,37,38].…”