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Comparative Transcriptomics Unravels Prodigiosin’s Potential Cancer-Specific Activity Between Human Small Airway Epithelial Cells and Lung Adenocarcinoma Cells

ABSTRACT: Objective: Non-small cell lung cancer (NSCLC) is extremely lethal upon metastasis and requires safe and effective systemic therapies to improve a patient’s prognosis. Prodigiosin (PG) appears to selectively and effectively target cancer but not healthy cells. However, PG’s cancer-specific activity has remained elusive until recently. Methods: PG’s cancer-specific performance was compared to Docetaxel (DTX), Paclitaxel (PTX), and Doxorubicin (DOX) against human lung adenocarcinoma (A549) and human small airway epithelial cells (HSAEC). Combination of PG with DTX, PTX, or DOX in a 1:1 ED50 ratio was also evaluated. MTT assay was used to determine the post-treatment cell viability. RNA-sequencing was used for comparative transcriptomics analysis between A549 and HSAEC treated with 1.0μM PG for 24 h. Results: PG reduced A549 cell viability by four-folds greater than HSAEC. In comparison to DTX, PTX and DOX, PG was ∼1.7 times more toxic toward A549, and 2.5 times more protective toward HSAEC. Combination of PG in 1:1 ED50 ratio with DTX, PTX, or DOX failed to exhibit synergistic toxicity toward A549 or protection toward HSAEC. In A549, genes associated in DNA replication were downregulated, while genes directly or indirectly associated in lipid and cholesterol biogenesis were upregulated. In HSAEC, co-upregulation of oncogenic and tumor suppressive genes was observed. Conclusion: An overactive lipid and cholesterol biogenesis could have caused A549’s autophagy while a balancing-act between genes of oncogenic and tumor-suppressive nature could have conferred HSAEC heightened survival. Overall, PG appears to be a smart chemotherapeutic agent that may be both safe and effective for NSCLC patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118448 | GEO | 2018/12/09

REPOSITORIES: GEO

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Project description:Non-small cell lung cancer (NSCLC) is the most lethal and prevalent type of lung cancer. In almost all types of cancer, the levels of polyamines (putrescine, spermidine, and spermine) are increased, playing a pivotal role in tumor proliferation. Indomethacin, a non-steroidal anti-inflammatory drug, increases the abundance of an enzyme termed spermidine/spermine-N1-acetyltransferase (SSAT) encoded by the SAT1 gene. This enzyme is a key player in the export of polyamines from the cell. The aim of this study was to compare the effect of indomethacin on two NSCLC cell lines, and their combinatory potential with polyamine-inhibitor drugs in NSCLC cell lines. A549 and H1299 NSCLC cells were exposed to indomethacin and evaluations included SAT1 expression, SSAT levels, and the metabolic status of cells. Moreover, the difference in polyamine synthesis enzymes among these cell lines as well as the synergistic effect of indomethacin and chemical inhibitors of the polyamine pathway enzymes on cell viability were investigated. Indomethacin increased the expression of SAT1 and levels of SSAT in both cell lines. In A549 cells, it significantly reduced the levels of putrescine and spermidine. However, in H1299 cells, the impact of treatment on the polyamine pathway was insignificant. Also, the metabolic features upstream of the polyamine pathway (i.e., ornithine and methionine) were increased. In A549 cells, the increase of ornithine correlated with the increase of several metabolites involved in the urea cycle. Evaluation of the levels of the polyamine synthesis enzymes showed that ornithine decarboxylase is increased in A549 cells, whereas S-adenosylmethionine-decarboxylase and polyamine oxidase are increased in H1299 cells. This observation correlated with relative resistance to polyamine synthesis inhibitors eflornithine and SAM486 (inhibitors of ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase, respectively), and MDL72527 (inhibitor of polyamine oxidase and spermine oxidase). Finally, indomethacin demonstrated a synergistic effect with MDL72527 in A549 cells and SAM486 in H1299 cells. Collectively, these results indicate that indomethacin alters polyamine metabolism in NSCLC cells and enhances the effect of polyamine synthesis inhibitors, such as MDL72527 or SAM486. However, this effect varies depending on the basal metabolic fingerprint of each type of cancer cell.

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Comparative Transcriptomics Unravels Prodigiosin’s Potential Cancer-Specific Activity Between Human Small Airway Epithelial Cells and Lung Adenocarcinoma Cells

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