Growth inhibitory role of the p53 activator SCH529074 in non‑small cell lung cancer cells expressing mutantp53.

Abstract

Mutations of p53 occur in approximately 50% of advanced non‑small cell lung cancer (NSCLC) cases, leading to loss of tumor suppressive function and/or gain of p53oncogenic activity. Reactivation of mutantp53 and consequently induction of apoptosis in cancer cells is the goal of p53‑targeted therapy. Recently, several p53mutant reactivating compounds were discovered including SCH529074. However, the role of SCH529074 in NSCLC has not been fully explored. In the present study, the effects of this compound on cell survival, cell cycle progression, induction of apoptosis and modulation of cell signaling in p53mutant NSCLCcells (H1975, H322 and H157) and p53 wild‑type NSCLCcells (A549), was investigated. Cell‑based functional assays, real‑time RT‑qPCR and western blot assays were used. HCT116 [p53 wild‑type (WT)] and HCT116 p53‑/‑ (p53null) were used as control cells. The results demonstrated that SCH529074 treatment caused significant reduction in cell viability and colony formation activity in p53mutant, p53WT and p53‑deficientcells. The treatment of NSCLC cells with SCH529074 resulted in a dose‑dependent induction of apoptosis and G0/G1 cell cycle arrest, which was associated with the activation of caspases(3and7), p53‑independent upregulation of p21 and PUMA as well as increased LC3II, a biomarker of autophagy. The combination treatment with the autophagy inhibitor chloroquine (CQ) and SCH529074 led to decreased cell viability, colony formation and increased induction of apoptosis. The data indicated that SCH529074 may exert its growth inhibitory function in a p53‑independent manner in NSCLCcells.