Overexpression of insulin-like growth factor binding protein-6 inhibits rhabdomyosarcoma growthin vivo

Abstract

Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood. Rhabdomyosarcoma cell lines overexpress insulin-like growth factor-II (IGF-II), an autocrine growth factor that is inhibited by insulin-like growth factor binding protein-6 (IGFBP-6). IGFBP-6 is associated with myoblast quiescence, and expression in rhabdomyosarcoma cells is low. The effect of IGFBP-6 on 2 rhabdomyosarcoma cell lines, RD and Rh30, was studied. IGFBP-6 inhibited anchorage-dependent growth of RD and Rh30 cells in a dosedependent manner (p < 0.0001). IGFBP-6 also inhibited anchorage-independent growth of RD cells in soft agar in a dose-dependent manner (p < 0.01). Anchorage-independent growth of RD cells on polyhydroxyethylmethacrylate-coated plates was decreased to a minimum of 48% of control after treatment with IGFBP-6 (p < 0.001). In this system, IGFBP-6 increased apoptosis 4-fold (p < 0.001). IGF-II partially reversed the IGFBP-6-induced decrease in growth and increase in apoptosis. Rh30 cells were stably transfected with an IG-FBP-6 cDNA and subcutaneous xenografts established in BALB/c nude mice. After 18 days, sizes of 2 independent clones of IGFBP-6-overexpressing Rh30 cells were reduced to 12% and 26% of vector control-transfected tumors (p ‫؍‬ 0.0006 and 0.002, respectively). IGFBP-6 therefore inhibits proliferation and promotes apoptosis of rhabdomyosarcoma in vitro and dramatically inhibits xenograft growth in vivo, at least in part by inhibiting IGF-II. Low expression of IGFBP-6 may therefore contribute to rhabdomyosarcoma growth and metastasis.

Insulin-like growth factor binding protein-6 inhibits prostate cancer cell proliferation: implication for anticancer effect of diethylstilbestrol in hormone refractory prostate cancer

“…They concluded that excess IGFBP-6 displaces IGF-II from IGFBP-2, thus preventing it from potentiating the mitogenic action of IGF-II (2002). Gallicchio et al (2001) also reported that IGFBP-6 dramatically inhibits xenograft growth of rhabdomyosarcoma cells.…”

“…In clinical practice, DES exerted its antitumour effect on androgen-independent prostate cancer (Takezawa et al, 2001). Furthermore, IGFBP-6 inhibited the proliferation of rhabdomyosarcoma cells (Gallicchio et al, 2001). These findings prompted us to study the effect of DES and IGFBP-6 on androgen-independent prostate cancer PC-3 cells.…”

“…However, the expression of IGFBP-6 and keratin 19 gene were upregulated in androgen-independent prostate cancer PC-3 cells. IGFBP-6 inhibits the proliferation of rhabdomyosarcoma cell lines (Gallicchio et al, 2001). Therefore, we characterised the biological action of IGFBP-6 in PC-3 cells.…”

“…IGF-II is an autocrine growth factor that affects neuroblastoma (Grellier et al, 2002) and rhabdomyosarcoma (Gallicchio et al, 2001) cells. In vivo, Grellier et al reported on the transplantation of human IGFBP-6-expressing neuroblastoma cells in nude mice, and their results showed a lower incidence of xenografts, which also exhibited slower growth than those obtained using control cells (1998).…”

Recent insights into the actions of IGFBP-6

“…Intranuclear actions were also implicated in apoptosis induced by IGFBP-6 (Iosef et al 2008(Iosef et al , 2010. As described above, IGFBP-6 overexpression inhibited rhabdomyosarcoma xenograft growth and angiogenesis in vivo Gallicchio et al 2001;Zhang et al 2012), and IGFBP-6 promotes rhabdomyosarcoma cell migration via pathways dependent on PHB2 and MAP kinase signalling (Fu et al 2007.…”