title: Perturbation of the Warburg effect increases the sensitivity of cancer cells to TRAIL-induced cell death.
abstract: Tumor necrosis-factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF-superfamily that selectively induces apoptosis through death receptors (DRs) 4 and/ or DR5 in cancer cells, without affecting normal cells. Unfortunately, many clinical studies have shown that cancer cells acquire TRAIL-resistance and thus avoid TRAIL-induced apoptosis. In the current study, we newly found that PTBP1, a splicer protein that plays an important role in energy metabolism is highly expressed in TRAIL-resistant human colon cancer DLD-1. Interestingly, silencing PTBP1 by using siRNA for PTBP1 (siR-PTBP1) resulted in a significant increase in TRAIL-sensitivity along with the switching of pyruvate kinase muscle (PKM) isoforms from PKM2 to PKM1, leading to impaired Warburg effect, because the intracellular ATP levels were significantly increased and the production of lactate decreased. Notably, siR-PTBP1 canceled the resistance by increasing the expression level of DR5 and effectively inducing the translocation of DR5 to the cell surface membrane. Also, siR-PTBP1 up-regulated the expression level of CCN1, which contributed to the enhanced sensitivity to TRAIL-induced apoptosis. These findings indicate that silencing PTBP1, thus impairing the Warburg effect positively affected TRAIL-induced apoptosis and that this splicer protein may thus serve as a possible target molecule to cancel the resistance of cancer cells to TRAIL.
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. Electronic address: t3501001@edu.gifu-u.ac.jp.
authors.forename: Minami
authors.initials: M
authors.lastname: Kumazaki
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Shinohara
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Takai
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kuranaga
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Sugito
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Akao
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D055515:Cysteine-Rich Protein 61 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects*; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000473:pathology*; D038941:Polypyrimidine Tract-Binding Protein / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D055515:Cysteine-Rich Protein 61; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C450006:PTBP1 protein, human; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D038941:Polypyrimidine Tract-Binding Protein; D000111:Acetylcysteine
keywords: CCN1; SiR-PTBP1; TRAIL-induced apoptosis; Warburg effect