Identification of cofilin-1 as a novel mediator for the metastatic potentials and chemoresistance of the prostate cancer cells.

Prostate cancer (PCa) is the most common malignancy among men. Tumor metastasis and chemoresistance contribute to the major cause of the mortality. In this study, we compared the protein profiles of two prostate cancer cell lines with different metastatic potentials, and identified cofilin-1 (CFL1) was one of the most differentially expressed proteins between two cell lines. Further results suggested that cofilin-1 promoted the remodeling of F-actin cytoskeleton, and enhanced the proliferation, migration and invasion of the prostate cancer cells via activation of P38 MAPK signaling pathway. In addition, cofilin-1 elevated the expression and drug efflux activity of multidrug resistance protein 1 (MDR1) by P38 MAPK signaling pathway, resulting in decrease of the adriamycin-induced apoptosis as well as the lytic cell death, and the subsequent resistance against adriamycin. Collectively, cofilin-1 might serve as a novel target candidate for both inhibiting the metastasis and reversing the chemoresistance of PCa.

Cisplatin induces chemoresistance through the PTGS2-mediated anti-apoptosis in gastric cancer.

It has been proposed that the aberrant expressions of the classical apoptosis-related genes and the subsequent decrease of apoptosis contribute to the development of cisplatin resistance in gastric cancer. However, little is known about the correlation and the molecular regulation mechanisms of cisplatin and the apoptosis-related gene expressions. Herein, we first identified the expressions of the anti-apoptotic BCL2 and the prostaglandin-endoperoxide synthase-2 (PTGS2) genes, which were abundant in the gastric carcinoma and associated with poor patient survival, were closely related with the resistance against cisplatin. Further investigations revealed that PTGS2 served as an essential mediator involved in the developing process of the resistance against cisplatin via mediating the inhibition effects of cisplatin on BCL2 expression. Mechanistically, cisplatin induced PTGS2 expression through ROS/NF-κB pathway. In addition, PTGS2 mediated cisplatin-induced BCL2 expression and subsequent resistance to apoptosis via PGE2/EP4/MAPKs (ERK1/2, P38) axis. Analysis of the clinical specimens demonstrated that PTGS2 and BCL2 were positively correlated in human gastric cancer. Moreover, in the xenograft models, inhibition of PTGS2 by celecoxib significantly augmented the cytotoxic efficacy of cisplatin in the resistant gastric cancer via suppression of PTGS2 and BCL2 expressions regulated by ERK1/2 and P38 signal axis, suggesting PTGS2 might be employed as an adjunctive therapeutic target for reversal of the chemoresistance in a subset of cisplatin resistant gastric cancer.

Identification of a crucial amino acid responsible for the loss of specifying FGFR1-KLB affinity of the iodinated FGF21.

Previous studies suggest that specific binding to the complex consisting of fibroblast growth factor receptor-1 (FGFR1) and the coreceptor beta-Klotho (KLB) is the premise for human FGF19 and FGF21 activating the downstream signaling cascades, and regulating the metabolic homeostasis. However, it was found that human FGF21 loses its ability to bind to FGFR1-KLB after iodination with Na125 I and chloramine T, whereas human FGF19 retained its affinity for FGFR1-KLB even after iodination. The molecular mechanisms underlying these differences remained elusive. In this study, we first demonstrated that an intramolecular disulfide bond was formed between cysteine-102 and cysteine-121 in FGF21, implying that the oxidation of the cysteine to cysteic acid, which may interfere with the active conformation of FGF21, did not occur during the iodination procedures, and thus ruled out the possibility of the two conserved cysteine residues mediating the loss of FGF21 binding affinity to FGFR1-KLB upon iodination. Site-directed mutagenesis and molecular modeling were further applied to determine the residue(s) responsible for the loss of FGFR1-KLB affinity. The results showed that mutation of a single tyrosine-207, but not the other five tyrosine residues in FGF21, to a phenylalanine retained the FGFR1-KLB affinity of FGF21 even after iodination, whereas replacing the corresponding phenylalanine residue with tyrosine in FGF19 did not alter its binding affinity to FGFR1-KLB, but decreased the receptor binding ability of the iodinated protein, suggesting that tyrosine-207 is the crucial amino acid responsible for the loss of specifying FGFR1-KLB affinity of the iodinated FGF21.

An FGF8b-mimicking peptide with potent antiangiogenic activity.

Fibroblast growth factor (FGF) 8b interacts with its receptors and promotes angiogenesis in hormone­dependent tumors. In the present study, we demonstrated that a short peptide, termed 8b­13, which mimics part of the FGF8b structure, significantly inhibited the proliferation and migration of human umbilical vein endothelial cells (HUVECs) triggered by FGF8b using 3­(4,5­dimethylthiazol­2­yl)­2,5­diphenyltetrazolium bromide (MTT), flow cytometry and an in vitro scratch assay. In addition, the findings from western blotting and reverse transcription­quantitative polymerase chain reaction revealed that 8b­13 appeared to counteract the effects of FGF8b on the expression of cyclin D1, the activation of signaling cascades, and the expression of proangiogenic factors; these actions may be involved in the mechanism underlying the inhibitory effects of 8b­13 on FGF8b­induced HUVEC proliferation and migration. The present results suggested that 8b­13 may be considered a potent FGF8b antagonist with antiangiogenic activity, and may have potential as a novel therapeutic agent for the treatment of cancer characterized by abnormal FGF8b upregulation.

Inhibition of autophagy promotes apoptosis and enhances anticancer efficacy of adriamycin via augmented ROS generation in prostate cancer cells.

The interplay between autophagy and apoptosis response to chemotherapy is still a subject of intense debate in recent years. More efforts have focused on the regulation effects of apoptosis on autophagy, whereas how autophagy affects apoptosis remains poorly understood. In this study performed on prostate cancer cells, we investigated the role of autophagy in adriamycin-induced apoptosis, as well as the mechanisms mediating the effects of autophagy on apoptosis response to adriamycin (ADM). The results show that ADM not only inhibited cell viability and enhanced apoptosis, but also promoted autophagy via PI3K/Akt(T308)/mTOR signal pathway. Inhibition of autophagy by either pharmacological inhibitor chloroquine (CQ) or RNA interference of Atg5 increased ADM-induced apoptosis and enhanced the chemosensitivity of prostate cancer cells. Moreover, blockade of autophagy augmented reactive oxygen species (ROS) generation induced by ADM. Scavenging of ROS by antioxidant N-acetyl-cysteine (NAC) reversed the strengthened effects of CQ on ADM-induced apoptosis and rescued the cells from apoptosis. The results identified ROS as a potential mediator directing the modulation effects of the protective autophagy on apoptosis response to ADM. Suppression of the protective autophagy might provide a promising strategy to increase the anticancer efficacy of agents in the treatment of prostate cancer.