Cofilin Drives Cell-Invasive and Metastatic Responses to TGF-β in Prostate Cancer

Abstract

Cofilin (CFL) is an F-actin–severing protein required for the cytoskeleton reorganization and filopodia formation, which drives cell migration. CFL binding and severing of F-actin is controlled by Ser3 phosphorylation, but the contributions of this step to cell migration during invasion and metastasis of cancer cells are unclear. In this study, we addressed the question in prostate cancer cells, including the response to TGF-β, a critical regulator of migration. In cells expressing wild-type CFL, TGF-β treatment increased LIMK-2 activity and cofilin phosphorylation, decreasing filopodia formation. Conversely, constitutively active CFL (SerAla) promoted filipodia formation and cell migration mediated by TGF-β. Notably, in cocultures of prostate cancer epithelial cells and cancer-associated fibroblasts, active CFL promoted invasive migration in response to TGF-β in the microenvironment. Further, constitutively active CFL elevated the metastatic ability of prostate cancer cells in vivo. We found that levels of active CFL correlated with metastasis in a mouse model of prostate tumor and that in human prostate cancer, CFL expression was increased significantly in metastatic tumors. Our findings show that the actin-severing protein CFL coordinates responses to TGF-β that are needed for invasive cancer migration and metastasis.

WITHDRAWN: Mechanisms navigating the TGF-β pathway in prostate cancer

“…Apigenin, a natural product belonging to the flavone, decreases VEGF expression by selectively inhibiting TGF-b1-induced phosphorylation of SMAD2 and SMAD3, further supporting the functional involvement of TGF-b in angiogenesis [62]. TGF-b exerts its regulatory role in angiogenesis, invasion and migration and EMT via navigating an array of interactions between tumor epithelial cells and myofibroblasts/CAFs maintaining a reactive tumor microenvironment, crucial to prostate cancer metastatic spread [21,59,63].…”

“…Recent studies from this laboratory established that constitutively active cofilin (Fig. 1) facilitated filopodia formation and cell migration induced as mediated by TGFb, and coordinated responses to TGF-b required for invasive cancer migration and metastasis [21].…”

“…In addition, SMAD7 induces proteasomal degradation of TGF-bRI, TGF-bRII, and other SMAD transcription factors to inhibit TGF-b signaling [19]. In addition to the SMAD dependent pathway, non-SMAD pathways, including MAPK, c-Src, m-TOR, RhoA, RAS, PI3K/Akt, protein phosphatase 2A/p70s6K [6,20], as well as the actin cytoskeleton effector cofilin [21,22] are regulated by TGF-b.…”

Over-expression of cofilin-1 suppressed growth and invasion of cancer cells is associated with up-regulation of let-7 microRNA

“…Accumulated evidence have supported that cofilin-1 should play a role in cancer progression [44,45]. Whether cofilin-1 over-expression can affect cancer progression in a small animal is rarely studied.…”

Localization of cofilin mRNA to the leading edge of migrating cells promotes directed cell migration

“…Its activity appears to synergize with Arp2/3 in generating lamellipodial protrusions, and is held in check by RhoC-mediated activation of LIM kinase that forms a boundary around invadopodia in invasive cells and protrusive lamellipodia in migrating cells (Bravo-Cordero et al, 2011;Zhang et al, 2011;Bravo-Cordero et al, 2013b). Constitutively active cofilin enhances the formation of lung tumors in nude mice injected with PC-3 prostate cancer cells in their tail vein (Collazo et al, 2014). Cofilin mRNA has been reported to be a target of VICKZ proteins (Piper et al, 2006;Jønson et al, 2007).…”