title: Upregulation of glucose metabolism by NF-κB2/p52 mediates enzalutamide resistance in castration-resistant prostate cancer cells.
abstract: Cancer cells reprogram their metabolic pathways to facilitate fast proliferation. Previous studies have shown that overexpression of NF-κB2/p52 (p52) in prostate cancer cells promotes cell growth and leads to castration resistance through aberrant activation of androgen receptor (AR). In addition, these cells become resistant to enzalutamide. In this study, we investigated the effects of p52 activation on glucose metabolism and on response to enzalutamide therapy. Data analysis of gene expression arrays showed that genes including GLUT1 (SLC2A1), PKM2, G6PD, and ME1 involved in the regulation of glucose metabolism were altered in LNCaP cells overexpressing p52 compared with the parental LNCaP cells. We demonstrated an increased amount of glucose flux in the glycolysis pathway, as well as the pentose phosphate pathway (PPP) upon p52 activation. The p52-overexpressing cells increase glucose uptake and are capable of higher ATP and lactate production compared with the parental LNCaP cells. The growth of p52-overexpressing cells depends on glucose in the culture media and is sensitive to glucose deprivation compared with the parental LNCaP cells. Targeting glucose metabolism by the glucose analog 2-deoxy-d-glucose synergistically inhibits cell growth when combined with enzalutamide, and resensitizes p52-overexpressing cells to enzalutamide treatment. These results suggest that p52 modulates glucose metabolism, enhances glucose flux to glycolysis and PPPs, thus facilitating fast proliferation of the cells. Co-targeting glucose metabolism together with AR axis synergistically inhibits cell growth and restores enzalutamide-resistant cells to enzalutamide treatment.
authors.affiliation: Department of Urology, University of California Davis Medical Center, 4645 2nd Avenue, Research, III, Suite 1300, Sacramento, California 95817, USA UC Davis Comprehensive Cancer Center, University of California Davis, California, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Cui
authors.forename: Nagalakshmi
authors.initials: N
authors.lastname: Nadiminty
authors.forename: Chengfei
authors.initials: C
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Lou
authors.forename: Chad T
authors.initials: CT
authors.lastname: Schwartz
authors.forename: Allen C
authors.initials: AC
authors.lastname: Gao
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001549:Benzamides; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007773:Lactates / Q000378:metabolism; D008297:Male; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism; D013549:Sweetening Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: C410798:AR protein, human; D001549:Benzamides; D007773:Lactates; D052003:NF-kappa B p52 Subunit; D009570:Nitriles; D011944:Receptors, Androgen; D013549:Sweetening Agents; D010669:Phenylthiohydantoin; D000255:Adenosine Triphosphate; C540278:enzalutamide; D005947:Glucose
keywords: NF-κB2/p52; enzalutamide; glucose metabolism; prostate cancer