Chemotherapy is an important treatment option for advanced prostate cancer, especially for metastatic prostate cancer (PCa). Resistance to first-line chemotherapeutic drugs such as docetaxel often acc Show more
Chemotherapy is an important treatment option for advanced prostate cancer, especially for metastatic prostate cancer (PCa). Resistance to first-line chemotherapeutic drugs such as docetaxel often accompanies prostate cancer progression. Attempts to overcome resistance to docetaxel by combining docetaxel with other biological agents have been mostly unsuccessful. A better understanding of the mechanisms underlying docetaxel resistance may provide new avenues for the treatment of advanced PCa. We have previously found that the fatty acid-binding protein 12 (FABP12)-PPARγ pathway modulates lipid-related bioenergetics and PCa metastatic transformation through induction of Slug, a master driver of epithelial-to-mesenchymal transition (EMT). Here, we report that the FABP12-Slug axis also underlies chemoresistance in PCa cells. Cell sensitivity to docetaxel is markedly suppressed in FABP12-expressing cells, along with induction of Survivin, a typical apoptosis inhibitor, and inhibition of cleaved PARP, a hallmark of programmed cell death. Importantly, Slug depletion down-regulates Survivin and restores cell sensitivity to docetaxel in FABP12-expressing cells. Finally, we also show that high levels of Survivin are associated with poor prognosis in PCa patients, with FABP12 status determining its prognostic significance. Our research identifies a FABP12-Slug-Survivin pathway driving docetaxel resistance in PCa cells, suggesting that targeting FABP12 may be a precision approach to improve chemodrug efficacy and curb metastatic progression in PCa. Show less
Lipoprotein lipase (LPL) is central to triglyceride metabolism. Severely compromised LPL activity causes familial chylomicronemia syndrome (FCS), which is associated with very high plasma triglyceride Show more
Lipoprotein lipase (LPL) is central to triglyceride metabolism. Severely compromised LPL activity causes familial chylomicronemia syndrome (FCS), which is associated with very high plasma triglyceride levels and increased risk of life-threatening pancreatitis. Currently, no approved pharmacological intervention can acutely lower plasma triglycerides in FCS. Low yield, high aggregation, and poor stability of recombinant LPL have thus far prevented development of enzyme replacement therapy. Recently, we showed that LPL monomers form 1:1 complexes with the LPL transporter glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) and solved the structure of the complex. In the present work, we further characterized the monomeric LPL/GPIHBP1 complex and its derivative, the LPL-GPIHBP1 fusion protein, with the goal of contributing to the development of an LPL enzyme replacement therapy. Fusion of LPL to GPIHBP1 increased yields of recombinant LPL, prevented LPL aggregation, stabilized LPL against spontaneous inactivation, and made it resistant to inactivation by the LPL antagonists angiopoietin-like protein 3 (ANGPTL3) or ANGPTL4. The high stability of the fusion protein enabled us to identify LPL amino acids that interact with ANGPTL4. Additionally, the LPL-GPIHBP1 fusion protein exhibited high enzyme activity in Show less