ACT001 inhibits the proliferation of non‐small cell lung cancer cells by upregulating NKTR expression

Abstract

Background Lung cancer, the primary cause of cancer‐related deaths worldwide, is diagnosed at an advanced stage and has a poor prognosis. Non‐small cell lung cancer (NSCLC) is a major histological type of lung malignancy. This study investigated the effect of ACT001, a novel sesquiterpene lactone derivative, on the proliferation of NSCLC cells and explored the underlying mechanism. Methods The effect of ACT001 on cell proliferation was examined by clone formation and MTT assay. Differentially expressed genes and enrichment pathways were analyzed by RNA‐seq. Flow cytometry and cell cycle‐related protein expression analysis were performed to study the cell cycle. Phosphorylated AKT was detected to explore the mechanism in natural killer cell triggering receptor (NKTR) KD cells with AKT activator and/or inhibitor. The therapeutic effect of ACT001 in vivo was studied in the xenograft tumor model. Results ACT001 inhibited the proliferation and G1/S transition in NSCLC cell lines. By RNA‐seq analysis, NKTR may be the target of ACT001. Moreover, knockdown NKTR promoted cell proliferation and reversed the effects of ACT001. In addition, ACT001 inhibited AKT phosphorylation, but NKTR knockdown promoted AKT phosphorylation. Conclusion Our results suggested NKTR may be the target of ACT001 in NSCLC. ACT001 holds promise as a novel method for the treatment of NSCLC.

ACT001 inhibits tumor progression and reduces the expression of PD-L1 in non-small cell lung cancer

“…Consistent with this obsergation, we found that ACT001 could also inhibit cell proliferation, migration, and invasiveness, while promote cell apoptosis in NSCLC. Besides, we veri ed the effect of ACT001 on cell cycle progression in NSCLC cells, and found ACT001 induce G1/S arrest which were similar to the results of Dingzhi Huang et al [19] .These results add new evidence supporting the anti-tumor effects of ACT001 in NSCLC.…”

“…While accumulating evidence attests to the anti-tumor effects of ACT001 across various cancer types, research speci cally targeting non-small cell lung cancer (NSCLC) remains limited. Recently, Dingzhi Huang et al demonstrated that ACT001 inhibited NSCLC cell proliferation by upregulating NKTR expression [19] . However, the anti-tumor effects of ACT001 and its underlying mechanisms remain poorly understood in NSCLC.…”

“…It promotes anti-in ammatory activation and limits M1 phenotype of pulmonary macrophages by inhibiting STAT1 and NF-κB signaling pathways [18] . Recently, it has been reported that ACT001 inhibits the proliferation of NSCLC cells by upregulating NKTR expression, which provides insights for NSCLC treatment [19] . However, the anti-tumor mechanism of ACT001 in NSCLC is still not fully understood.…”

ACT001 inhibits the proliferation of tumor cells and improves immune function in multiple myeloma.

“…It has even been shown that ACT001 inhibits the G1/S transition in NSCLC cell lines. [25] Then in validating proteins in the apoptotic and proliferative pathways of myeloma cells, we found that in addition to the phosphorylated proteins, total STAT3 and NF-KB were also almost decreasing with increasing drug concentration. This appears to be a small divergence from the results of the existing studies.…”

“…[24] The antitumor effects of ACT001 have also been reported in non-small cell lung cancer, human breast cancer, and pancreatic ductal adenocarcinoma. [25,26,27] From the analysis of existing studies, in addition to anti-tumor effects, it is speculated that ACT001 a multi-targeted small molecule immune-inflammatory modulator.ACT001 inhibits nuclear translocation of NFκB in microglia by inhibiting AKT phosphorylation, which reduces the activation of the NLRP3 inflammasome, and ultimately down-regulates the neuroinflammatory response in microglia. [28]Similar results were confirmed in radiation-induced lung injury (RILI), [29]and even ACT001 alleviated NLRP3-mediated neuroinflammation in Parkinson's disease mice.…”