title: Downregulation of oncogenic RAS and c-Myc expression in MOLT-4 leukaemia cells by a salicylaldehyde semicarbazone copper(II) complex.
abstract: Copper complexes with potent anti-tumor effect have been extensively developed. Most investigations of their modes of action focused on the biomolecular targets but not the signal transduction between target binding and cell death. We have previously shown that the cytotoxic complex pyridine(2,4-dihydroxybenzaldehyde dibenzyl semicarbazone)copper(II) (complex 1) shows selective binding to human telomeric G-quadruplex DNA over double-stranded DNA in vitro. Herein, we elucidate the mechanism of action by which complex 1 induces apoptosis in MOLT-4 cells. Complex 1 accumulates in the nuclei and differentially downregulates the expression of c-Myc, c-Kit and KRAS oncogenes. Chemical affinity capture assay results show that the complex is associated with c-Myc and KRAS quadruplex sequences in MOLT-4 cells. We further showed that the reduction in Ras protein expression resulted in attenuated MEK-ERK and PI3K-Akt signalling activities, leading to the activation of caspase-dependent apoptosis. Notably, complex 1 increased the sensitivity of MOLT-4 cells to cisplatin and vice versa. Overall, we demonstrated that complex 1 induces apoptosis, at least in part, by suppressing KRAS, c-Kit and c-Myc oncogene expression and the pro-survival MEK-ERK and PI3K-Akt signalling pathways.
authors.affiliation: Natural Sciences &Science Education, National Institute of Education, Nanyang Technological University, 1 Nanyang Walk, Singapore 637616, Singapore.
authors.forename: Yan-Yih
authors.initials: YY
authors.lastname: Goh
authors.affiliation: Natural Sciences &Science Education, National Institute of Education, Nanyang Technological University, 1 Nanyang Walk, Singapore 637616, Singapore.
authors.forename: Yaw-Kai
authors.initials: YK
authors.lastname: Yan
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551.|Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Avenue, Singapore 639798, Singapore.|Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673, Singapore.|KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore.
authors.forename: Nguan Soon
authors.initials: NS
authors.lastname: Tan
authors.affiliation: Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Su-Ann
authors.initials: SA
authors.lastname: Goh
authors.affiliation: Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
authors.forename: Shang
authors.initials: S
authors.lastname: Li
authors.affiliation: Natural Sciences &Science Education, National Institute of Education, Nanyang Technological University, 1 Nanyang Walk, Singapore 637616, Singapore.
authors.forename: You-Chuan
authors.initials: YC
authors.lastname: Teoh
authors.affiliation: Singapore Institute of Technology, 10 Dover Drive, Singapore 138683, Singapore.
authors.forename: Peter P F
authors.initials: PP
authors.lastname: Lee
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009942:Organometallic Compounds / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D012664:Semicarbazones / Q000494:pharmacology*
chemical_list: C117307:KRAS protein, human; C489427:MYC protein, human; D009942:Organometallic Compounds; D016271:Proto-Oncogene Proteins c-myc; D012664:Semicarbazones; D016283:Proto-Oncogene Proteins p21(ras); D002945:Cisplatin