Lung Adenocarcinoma Cell Sensitivity to Chemotherapies: A Spotlight on Lipid Droplets and SREBF1 Gene

Simple Summary The accumulation of lipid droplets (LDs) and the high expression of genes involved in LD formation, such as SREBF1 (sterol regulatory element binding transcription factor 1), are attributed to cancer cell resistance against anticancer drugs and poor prognosis. We assessed lung cancer cells with and without LDs for their sensitivity to chemotherapeutics cisplatin and etoposide. In either serum-free basal medium or inflammatory supernatants generated during neutrophil degranulation in vitro, both drugs strongly reduced SREBF1 expression, which did not parallel with LD formation and cell sensitivity to chemotherapeutics. Nevertheless, under basal conditions, SREBF1 expression in cancer cells correlated with LD levels, and the lower expression of SREBF1 in tumors than in adjacent nontumor tissues showed a prognostic value for overall better survival of patients with non-small-cell lung cancer. Strategies targeting lipid metabolism in cancer are promising therapeutic and/or diagnostic approaches. To explore the relationship between cancer cell SREBF1 expression, lipid droplets (LDs) formation, and the sensitivity to chemotherapies, we cultured lung adenocarcinoma cells H1299 (with LD) and H1563 (without LD) in a serum-free basal medium (BM) or neutrophil degranulation products containing medium (NDM), and tested cell responses to cisplatin and etoposide. By using the DESeq2 Bioconductor package, we detected 674 differentially expressed genes (DEGs) associated with NDM/BM differences between two cell lines, many of these genes were associated with the regulation of sterol and cholesterol biosynthesis processes. Specifically, SREBF1 markedly declined in both cell lines cultured in NDM or when treated with chemotherapeutics. Despite the latter, H1563 exhibited LD formation and resistance to etoposide, but not to cisplatin. Although H1299 cells preserved LDs, these cells were similarly sensitive to both drugs. In a cohort of 292 patients with non-small-cell lung cancer, a lower SREBF1 expression in tumors than in adjacent nontumor tissue correlated with overall better survival, specifically in patients with adenocarcinoma at stage I. Our findings imply that a direct correlation between SREBF1 and LD accumulation can be lost due to the changes in cancer cell environment and/or chemotherapy. The role of LDs in lung cancer development and response to therapies remains to be examined in more detail.