Arsenic sulfide reverses cisplatin resistance in non-small cell lung cancer in vitro and in vivo through targeting PD-L1

Abstract

Background: Recent studies have found that programmed death ligand 1 (PD-L1) might be involved in chemotherapy resistance in non-small cell lung cancer (NSCLC). Arsenic sulfide (As₄ S₄ ) has been recognized to have antitumor activities and enhance the cytotoxic effect of chemotherapy drugs. In this study, we aimed to verify the relationship between PD-L1 and cisplatin (DDP) resistance and identify whether As₄ S₄ could reverse DDP resistance through targeting PD-L1 in NSCLC.

Methods: The effect of As₄ S₄ and DDP on cell proliferation and apoptosis was investigated in NSCLC cell lines. The expression of p53 and PD-L1 proteins was measured by western blotting analysis. The levels of miR-34a-5p, miR-34a-3p and PD-L1 in cells were measured by real-time qPCR analysis. Mouse xenograft models were established by inoculation with A549/DDP (DDP-resistant) cells.

Results: Depletion of PD-L1 inhibited DDP resistance in A549/DDP and H1299/DDP cells. As₄ S₄ was capable of sensitizing A549/DDP cells to DDP by enhancing apoptosis. As₄ S₄ upregulated p53 expression and downregulated PD-L1 expression in A549/DDP cells. As₄ S₄ increased miR-34a-5p level in A549/DDP cells. Inhibition of p53 by PFT-α partially restored the levels of PD-L1 and miR-34a-5p. Pretreatment with PFT-α suppressed the apoptosis rate induced by cotreatment of As₄ S₄ and DDP in A549/DDP cells. Cotreatment of DDP and As₄ S₄ notably reduced the tumor size when compared with DDP treatment alone in vivo.

Conclusions: Upregulation of PD-L1 was correlated with DDP resistance in NSCLC cells. Mechanistic analyses indicated that As₄ S₄ might sensitize NSCLC cells to DDP through targeting p53/miR-34a-5p/PD-L1 axis.

Keywords: As4S4; NSCLC; PD-L1; chemoresistance; cisplatin.