Vitamin D promotes anticancer effects of low-concentration cisplatin-treated non-small cell lung cancer cells via inhibiting the JAK2/STAT3 and TGF-β/SMAD4 pathways

Abstract

Lung cancer is one of the most fatal kinds of cancer, with low survival rate because of delayed discovery and traditional therapy failure. This study intends to determine whether cisplatin plus vitamin D could be a more successful combination than standard monotherapy for non-small-cell lung cancer (NSCLC) by targeting the transforming growth factor beta (TGF-β)/mothers against decapentaplegic homolog 4 (SMAD4) and janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathways and their downstream targets. Cytotoxic effects of vitamin D on MCF-7, MCFR-10, H1299, A549, and PC3 cell lines were evaluated by sulforhodamine-B (SRB) assay, indicating that H1299 and A549 were the most effected cell lines; hence, they were selected for more investigation. IC₅₀ values of cisplatin against H1299 and A549 cells were established. Quantitative polymerase chain reaction (qPCR) was used to assess the expression levels of JAK2, STAT3, TGF-β, Smad4, matrix metalloproteinase-2 (MMP-2), and MMP-9 in both cell lines treated with vitamin D, cisplatin, or both. Results demonstrated remarkable expression of the aforementioned genes in H1299 and A549 cells, which was sharply decreased once the combination treatment was administered. Additionally, the protein expression of VEGF, MMP9, and angiotensin I, II is considerably inhibited by this combination. According to the obtained data, vitamin D and cisplatin combination therapy can target genes and proteins involved in cell adhesion, migration, and invasion.