The inhibition of ACLY induces
The inhibition of ACLY induces an anticancer effect that has been reported to be involved in mitochondrial reactive oxygen species (ROS) generation , , dual blockade of mitogen-activated protein kinase and phosphatidylinositol-3-kinase/AKT pathways , and the glycolytic phenotype of tumor . More recently, Lei et al. reported that ACLY acetylation stabilizes ACLY and promotes the development of lung cancer . CuB has been revealed as a multitargeted cancer chemopreventive and chemotherapeutic agent. The mechanisms underlying CuB-induced apoptosis are associated with the signal transducer and activator of transcription, cyclooxygenase-2, BRCA1, p34CDC2/Cyclin B1 complex, ROS regulation , , , , , , , , , , , , , , , , and the disruption of microtubule polymerization and nucleophosmin/B23 translocation . Our present data showed that CuB treatment induced mitochondrial ROS generation in human prostate cancer cells. However, the CuB-induced mitochondrial ROS production and apoptosis as well as ACLY inhibition were almost completely blocked by NAC treatment. These results suggest that mitochondrial ROS-dependent ACLY signaling is involved in CuB-induced apoptotic cell death in our models.
The proapoptotic Bcl-2 family proteins, which can be subdivided into the Bax subfamily of multidomain proteins (e.g., Bax and Bak) or BH3-only subfamily (e.g., Bid and Bim), induce mitochondrial membrane permeabilization and release of apoptogenic molecules from mitochondria to the cytosol . A down-regulation of Bcl-2 and Survivin protein expressions (PC-3 and LNCaP) and an increase in protein levels of Bax (LNCaP) and Bim-S (LNCaP) were observed in our present study (Fig. S2). Furthermore, CuB treatment resulted in a remarkable cleavage of Mcl-1 protein in both PC-3 and LNCaP (±)-Baclofen (Fig. S2). The present study indicates that the multidomain proapoptotic Bcl-2 family members Bax/Bim and/or antiapoptic Bcl-2 family members Bcl-2 and Mcl-1 play a critical role in regulation of CuB-induced apoptosis. Therefore, further studies are needed to determine the role of antiapoptotic Bcl-2 family members, such as Bcl-2 and Mcl-1 in regulation of CuB-mediated cell death in prostate cancer cells.
Conclusion We are the first to report that CuB is a potent inhibitor of prostate cancer cell growth both in vitro and in vivo. Our present study reveals a novel mechanism of CuB-anticancer activity namely, that ACLY plays an important role in CuB-induced apoptotic cell death in human prostate cancer. To our knowledge, this is the first study to report that a natural compound inhibited cancer growth by inactivation of ACLY signaling. Therefore, CuB could potentially be useful as a leading compound for future anti-prostate cancer research, as well as for clinical studies that aim to investigate prostate cancer prevention and therapy.
Conflict of Interest
Acknowledgments The authors thank Drs. Joel Nelson and Zhou Wang of Department of Urology and Department of Urology Research for their support. The research related to this article is partially supported by the National Institutes of Health National Cancer Institute and Office of Dietary Supplements Grant RO1-CA157477 to D.X.
Introduction Utilization of microbial oils as a substrate for biofuel production represents a promising way to face global change and rarefaction of petroleum resources. Few micro-organisms are able to produce a high level of oil , . Among them, yeasts have emerged as good candidates , , because they are easy to cultivate, to manipulate genetically and they have a high lipid accumulation potential. For this reason, improvement of fatty acid (FA) accumulation in yeasts has become a very important topic in recent years , , , , , , ,  and will be probably still of high importance in the next years. FA is produced by the Fatty Acid Synthase (FAS) from acetyl-CoA, malonyl-CoA and NADPH. For several decades, provision of acetyl-CoA and NADPH has been attributed to ATP-citrate lyase (Acl) and malic enzyme (Mae), respectively , . However, the role of these two major enzymes appears not so clear, depending in which organism is being studied.