HIF-1/AKT Signaling-Activated PFKFB2 Alleviates Cardiac Dysfunction and Cardiomyocyte Apoptosis in Response to Hypoxia.

Myocardial infarction (MI) is the most prevalent disease with severe mortality, and hypoxia-induced cardiac injury and cardiomyocyte apoptosis are the significant and harmful consequences of this disease. The cross talk between hypoxia signaling and glycolysis energy flux plays a critical role in modulating MI-related heart disorder. However, the underlying mechanism remains unclear. Here, we aimed to explore the effect of a key glycolytic enzyme of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 2 (PFKFB2) on cardiac dysfunction and apoptosis in response to hypoxia. Our data demonstrated that the mRNA and protein expression of PFKFB2 were significantly elevated in the MI mice. The MI treatment promoted the activation of PFKFB2 in vivo, as presented by the remarkably increased phosphorylation levels of PFKFB2. PFKFB2 depletion enhanced MI-induced cardiac dysfunction and cardiomyocyte apoptosis in the MI mouse model. Moreover, hypoxia treatment dramatically upregulated the expression and activation of PFKFB2 in a time-dependent manner in cardiomyocytes. Hypoxia-stimulated PFKFB2 relieved hypoxia-induced cardiomyocyte apoptosis in vitro. PFKFB2 activated the fructose-2, 6-bisphosphate (Fru-2, 6-p2) /PFK/anaerobic adenosine triphosphate (ATP) glycolysis energy flux in response to hypoxia in cardiomyocytes. Mechanically, hypoxia-activated PFKFB2 by stimulating the hypoxia-inducible factor 1 (HIF-1) /ATK signaling. Thus, we conclude that HIF-1/AKT axis-activated PFKFB2 alleviates cardiac dysfunction and cardiomyocyte apoptosis in response to hypoxia. Our finding presents a new insight into the mechanism by which HIF-1/AKT/PFKFB2 signaling modulates MI-related heart disorder under the hypoxia condition, providing potential therapeutic targets and strategy for hypoxia-related myocardial injury.

Osteopontin accelerates the development and metastasis of bladder cancer via activating JAK1/STAT1 pathway.

BACKGROUND: Bladder cancer is the 10th common cancer worldwide. Osteopontin has been found to enhance cell proliferation, metastasis and invasion in various human tumors. OBJECTIVE: To investigate the roles of osteopontin in bladder cancer. METHODS: The RNA interference and overexpression of osteopontin were performed in bladder cancer cell lines (T24 and SCaBER). Cell proliferation and apoptosis were measured using CCK-8 assay and flow cytometry, respectively. Cell invasion was determined using transwell assay. RESULTS: Osteopontin was highly expressed in bladder cancer tissues in comparison with the adjacent normal tissues. Its high expression significantly correlated with high histologic grade, high TNM stage (III and IV) and poor prognosis. For T24 cells with osteopontin interference and SCaBER cells with osteopontin overexpression, cell proliferation was significantly inhibited (3.58-fold vs. 5.62-fold) and enhanced (7.81-fold vs. 5.29-fold), respectively. The apoptosis portion of T24 cells significantly increased from 4.48 to 10.75%, and that of SCaBER cells significantly declined from 7.33 to 4.01%. The invaded T24 and SCaBER cells significantly decreased to 52.0% and increased to 2.0-fold, respectively. Osteopontin overexpression enhanced the expression (1.54-fold and 2.39-fold; 2.33-fold and 2.05-fold) and activation (1.80-fold and 1.96-fold; 2.00-fold and 2.59-fold) of JAK1 and STAT1 in two cell lines of bladder cancer. CONCLUSION: Osteopontin might enhance proliferation, inhibit apoptosis and accelerate invasion and thus promote the development and metastasis of bladder cancer, and osteopontin's functions might be mediated by activating JAK1/STAT1 signaling pathway.

HBP21: a novel member of TPR motif family, as a potential chaperone of heat shock protein 70 in proliferative vitreoretinopathy (PVR) and breast cancer.

A large number of tetratricopeptide repeat (TPR)-containing proteins have been shown to interact with the C-terminal domain of the 70 kDa heat-shock protein (Hsp70), especially those with three consecutive TPR motifs. The TPR motifs in these proteins are necessary and sufficient for mediating the interaction with Hsp70. Here, we investigate HBP21, a novel human protein of unknown function having three tandem TPR motifs predicted by computational sequence analysis. We confirmed the high expression of HBP21 in breast cancer and proliferative vitreoretinopathy (PVR) proliferative membrane and examined whether HBP21 could interact with Hsp70 using a yeast two-hybrid system and glutathione S-transferase pull-down assay. Previous studies have demonstrated the importance of Hsp70 C-terminal residues EEVD and PTIEEVD for interaction with TPR-containing proteins. Here, we tested an assortment of truncation and amino acid substitution mutants of Hsp70 to determine their ability to bind to HBP21 using a yeast two-hybrid system. The newly discovered interaction between HBP21 and Hsp70 along with observations from other studies leads to our hypothesis that HBP21 may be involved in the inhibition of progression and metastasis of tumor cells.