Enhanced G1 arrest and apoptosis via MDM4/MDM2 double knockdown and MEK inhibition in wild‑type TP53 colon and gastric cancer cells with aberrant KRAS signaling

Murine double minute homolog 2 (MDM2) is an oncoprotein that induces p53 degradation via ubiquitin‑ligase activity. MDM4 cooperates with MDM2‑mediated degradation, directly inhibiting transcription by binding to its transactivation domain. Our previous study reported the simultaneous inhibition of MDM2 and using nutlin‑3 (an inhibitor MDM2‑p53 interaction) chimeric small interfering RNA DNA‑substituted seed arms (named chiMDM2 chiMDM4) more potently activated than or alone synergistically augmented antitumor effects in various types cancer cells wild‑type (wt) TP53. Recently, synergism mitogen‑activated protein kinase (MEK) inhibitors has been demonstrated wt TP53 colorectal non‑small cell lung harboring mutant‑type (mt) KRAS. The current examined whether chiMDM4 synergistic MEK trametinib, respectively. ChiMDM2 trametinib used combination a activity HCT116 LoVo colon cells, SNU‑1 gastric mt Furthermore, enhanced this combinational effect. Similar results were observed when was instead chiMDM2. MDM4/MDM2 knockdown combined treatment G1 arrest apoptosis induction. This associated accumulation p53, suppression phosphorylated‑extracellular signal‑regulated 2, retinoblastoma phosphorylation, E2F1‑activated proteins, potent activation pro‑apoptotic such as Fas upregulated modulator apoptosis. inidcated triple MDM4, exerted effect Simultaneous aberrant KRAS signaling may be rational strategy for gastrointestinal tumors.