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.

G-Quadruplex: A Regulator of Gene Expression and Its Chemical Targeting

“…The mechanism described in this study suggested more extensive roles for G4 regulation in complicated antitumor therapies. 92 Similar to the idea of targeting and manipulating multiple G4 targets, some strategies that simultaneously targeted G4 motifs and the i-motif have also been reported recently. It is known that G4s are not the only secondary structures in cells; hairpin structures, for example, are common.…”

Whole-Transcriptome Profiling of Canine and Human in Vitro Models Exposed to a G-Quadruplex Binding Small Molecule

“…In Goh et al . (2016), a salicylaldehyde semicarbazone copper (II) complex induced apoptosis through the caspase-dependent pathway by reducing the expression of RAS and MYC , and by inhibiting Ras-ERK and PI3K-Akt pathways in MOLT-4 leukemia cells 48 . In 2013, Shen and colleagues proved that a G4 ligand named SYUIQ-FM05 suppressed KIT mRNA transcription and total kit protein amount in K562 cells, and this inhibition led to a downregulation of MEK activity, ERK phosphorylation, and the RAS/MEK/ERK signaling pathway 49 .…”

Myoblast Myogenic Differentiation but Not Fusion Process Is Inhibited via MyoD Tetraplex Interaction

“…Small molecules that stabilize one of the possible 3D shapes of the G-quartets have been hypothesized as tools for antineoplastic function, for example, to block promoters containing tetraplex consensus [ 14 – 16 ]. The oncogenes c-myc, bcl2, and kRAS, the dystrophy gene DMPK, the transcription factor Oct4, and the topoisomerase-1 are all putative targets of those tetraplex-interacting molecules as part of potential clinical care [ 17 – 20 ]. TMPyP4 is one of those molecules, as it is a cationic porphyrin that is known mainly as a DNA tetraplex stabilizer, which is largely used for in vitro analysis [ 21 ].…”