The acquisition of ectopic fibroblast growthfactor receptor 1 (FGFR1) expression is well documented in prostate cancer progression. How it contributes to prostate cancer progression is not fully understood, although it is known to confer a growth advantage and promote cell survival. Here, we report that FGFR1 tyrosine kinase reprograms the energy metabolism of prostate cancer cells by regulating the expression of lactate dehydrogenase (LDH) isozymes. FGFR1 increased LDHA stability through tyrosine phosphorylation and reduced LDHB expression by promoting its promoter methylation, thereby shifting cell metabolism from oxidative phosphorylation to aerobic glycolysis. LDHA depletion compromised, whereas LDHB depletion enhanced the tumorigenicity of prostate cancer cells. Furthermore, FGFR1 overexpression and aberrant LDH isozyme expression were associated with short overall survival and biochemical recurrence times in patients with prostate cancer. Our results indicate that ectopic FGFR1 expression reprograms the energy metabolism of prostate cancer cells, representing a hallmark change in prostate cancer progression. FGF signaling drives the Warburg effect through differential regulation of LDHA and LDHB, thereby promoting the progression of prostate cancer. http://cancerres.aacrjournals.org/content/canres/78/16/4459/F1.large.jpg .

Sonic Hedgehog signaling is critical for breast morphogenesis and cancer. The present study was conducted to explore the influence of SHH/GLI1 axis on epithelial mesenchymal transition and invasion in breast cancer cells. SHH/GLI1 positive samples demonstrated high expression of Snail and Vimentin with relatively low expression of E-cadherin. Overexpression of Vimentin and Snail in SHH/GLI1 positive patients was also associated with poor overall survival. Interestingly, GANT61 (GLI1 inhibitor) exposure significantly reduced cell viability and induced apoptosis at 10 µM. Suppression of Hedgehog pathway either by CRISPR mediated SHH knock out or GANT61 altered regulation of EMT markers in breast cancer cells. Moreover, in-activation of SHH/GLI1 axis also significantly restricted cell migration and invasiveness. These findings suggest that targeting SHH/GLI1 axis alters expression of EMT markers and abrogates neoplastic invasion in breast cancer cells.

Initiation of expression of fibroblast growth factor receptor 1 (FGFR1) concurrent with loss of FGFR2 expression is a well-documented event in the progression of prostate cancer (PCa). Although it is known that some FGFR isoforms confer advantages in cell proliferation and survival, the mechanism by which the subversion of different FGFR isoforms contributes to PCa progression is incompletely understood. Here, we report that fibroblast growth factor (FGF) promotes NF-κB signaling in PCa cells and that this increase is associated with FGFR1 expression. Disruption of FGFR1 kinase activity abrogated both FGF activity and NF-κB signaling in PCa cells. Of note, the three common signaling pathways downstream of FGFR1 kinase, extracellular signal-regulated kinase 1/2 (ERK1/2), phosphoinositide 3-kinase (PI3K/AKT), and phosphoinositide phospholipase Cγ (PLCγ), were not required for FGF-mediated NF-κB signaling. Instead, transforming growth factor β-activating kinase 1 (TAK1), a central regulator of the NF-κB pathway, was required for FGFR1 to stimulate NF-κB signaling. Moreover, we found that FGFR1 promotes NF-κB signaling in PCa cells by reducing TAK1 degradation and thereby supporting sustained NF-κB activation. Consistently, Fgfr1 ablation in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model reduced inflammation in the tumor microenvironment. In contrast, activation of the FGFR1 kinase in the juxtaposition of chemical-induced dimerization (CID) and kinase 1 (JOCK1) mouse model increased inflammation. As inflammation plays an important role in PCa initiation and progression, these findings suggest that ectopically expressed FGFR1 promotes PCa progression, at least in part, by increasing inflammation in the tumor microenvironment.

Herein, for the first time, we report a "green", one-pot reduction/decoration method for the synthesis of bifunctional adsorbent-catalytic hemin-graphene nanosheets by using a common available protein (bovine serum albumin, BSA) as both a reductant and a stabilizer. Our prepared nanosheets are highly stable and possess intrinsic peroxidase-like catalytic activity due to the decoration of BSA and hemin. Furthermore, benefiting from the combined advantages of graphene and BSA, these nanosheets are able to efficiently adsorb dye pollutants from aqueous solution. More importantly, due to their adsorption and catalytic ability, these adsorbent-catalytic nanosheets can be applied to highly efficient dye removal via synergistic adsorption and degradation. Specifically, our catalysts can easily bring organic dyes to their surface by adsorption, and then activate HO to generate hydroxyl radicals, leading to the degradation of the dyes. Such catalytic mechanism of our as-prepared nanosheets was analogous to that of natural enzymes, in which the extremely high catalytic efficiency is largely dependent upon their ability to bring substrates in close proximity to the active sites of enzymes. Our finding may open new potential applications of hemin-graphene hybrid nanosheets in environmental chemistry, biotechnology, and medicine.

Advanced castrate-resistant prostate cancer (CRPC) is a poorly prognostic disease currently lacking effective cure. Understanding the molecular mechanism that underlies the initiation and progression of CRPC will provide new strategies for treating this deadly disease. One candidate target is the fibroblast growth factor (FGF) signaling axis. Loss of the intrinsic FGF7/FGF10-type 2 FGF receptor (FGFR2) pathway and gain of the ectopic type 1 FGF receptor (FGFR1) pathway are associated with the progression to malignancy in prostate cancer (PCa) and many other epithelial originating lesions. Although FGFR1 and FGFR2 share similar amino acid sequences and structural domains, the two transmembrane tyrosine kinases elicit distinctive, even sometime opposite signals in cells. Recent studies have revealed that the ectopic FGFR1 signaling pathway contributes to PCa progression via multiple mechanisms, including promoting tumor angiogenesis, reprogramming cancer cell metabolism, and potentiating inflammation in the tumor microenvironment. Thus, suppression of FGFR1 signaling can be an effective novel strategy to treat CRPC.