Nuclear translocation of fibroblast growth factor-2 (FGF2) is regulated by Karyopherin-β2 and Ran GTPase in human glioblastoma cells

Abstract

Human glioblastoma multiforme (GBM) is the most malignant tumor of the central nervous system (CNS). Fibroblast growth factor-2 (FGF2) belongs to the FGF superfamily and functions as a potential oncoprotein in GBM. FGF2 has low molecular weight (18K) and high molecular weight (HMW) isoforms. Nuclear accumulation of HMW-FGF2 strongly promotes glioblastoma cell proliferation, yet mechanism governing such cellular distribution remains unexplored. We investigated the mechanisms regulating FGF2 cellular localization in T98G human brain glioblastoma cells. We found HMW-FGF2, but not 18K-FGF2, is primarily located in the nucleus and interacts with nuclear transport protein Karyopherin-β2/Transportin (Kapβ2). SiRNA-directed Kapβ2 knockdown significantly reduced HMW-FGF2′s nuclear translocation. Moreover, inhibiting Ran GTPase activity also resulted in decreased HMW-FGF2 nuclear accumulation. Proliferation of T98G cells is greatly enhanced with transfections HMW-FGF2. Decreased PTEN expression and activated Akt signaling were observed upon HMW-FGF2 overexpression and might mediate pro-survival effect of FGF2. Interestingly, addition of nuclear localization signal (NLS) to 18K-FGF2 forced its nuclear import and dramatically increased cell proliferation and Akt activation. These findings demonstrated for the first time the molecular mechanisms for FGF2′s nuclear import, which promotes GBM cell proliferation and survival, providing novel insights to the development of GBM treatments.

Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling

“…The use of FGF traps as inhibitors of FGF/FGFR signaling in MM cells has shown the FGF/FGFR signaling axis is required for stabilization of the oncoprotein, transcription factor c-MYC and subsequent resistance to mitochondrial oxidative stress induced apoptosis, which is critical in tumor progression [ 145 , 146 ]. Nuclear activity of a heavy molecular weight FGF2 (hmwFGF2) [ 147 ] has been implicated in promoting cell proliferation and survival in glioma [ 148 , 149 ], in glioma cells, and indirectly through nuclear localization in astrocytes [ 149 ]. It is likely that nuclear hmwFGF2 induces this effect partly through decreased expression of tumor suppressor phosphatase and tensin homolog (PTEN), as well as increased AKT activity [ 148 ].…”

“…Nuclear activity of a heavy molecular weight FGF2 (hmwFGF2) [ 147 ] has been implicated in promoting cell proliferation and survival in glioma [ 148 , 149 ], in glioma cells, and indirectly through nuclear localization in astrocytes [ 149 ]. It is likely that nuclear hmwFGF2 induces this effect partly through decreased expression of tumor suppressor phosphatase and tensin homolog (PTEN), as well as increased AKT activity [ 148 ]. Low molecular weight (lmw) FGF2-FGFR1 colocalization in the nucleus, and subsequent activity in pancreatic stellate cells (PSCs), promotes proliferation and PSC-mediated pancreatic cancer cell invasion [ 150 ].…”

FGF‐2 and FGFR‐1 might be independent prognostic factors in oral tongue squamous cell carcinoma

“…Under homeostatic situations, fibroblast growth factor receptor (FGFR)‐1 is signalled by growth factors, such as FGF‐2 . Changes in the FGF‐2–FGFR‐1 pathway have been identified in several types of cancer, including non‐small‐cell lung cancer, breast cancer, oesophageal cancer, lymphoma, hepatocellular carcinoma, and glioblastoma . Although the roles of FGF‐2 and FGFR‐1 in OSCC tumorigenicity and metastasis progression have previously been investigated, mainly with experimental models, few studies have evaluated the impact of these markers on the outcome of patients with oral cancer …”

The association of RAN and RANBP2 gene polymerphisms with Wilms tumor risk in Chinese children

“…Several researches illustrated that RAN-inhibitory peptide-loaded PEG-PLGA NPs have great potential in curbing cancer through limiting the formation of active forms of RAN [32][33][34]. In addition, the expression level of RAN was significantly altered in glioblastoma, pancreatic cancer, neuroblastoma, melanoma [35][36][37][38][39][40].…”