Paclitaxel-resistant cancer cell-derived secretomes elicit ABCB1-associated docetaxel cross-resistance and escape from apoptosis through FOXO3a-driven glycolytic regulation

Chemotherapy-induced cancer cell secretomes promote resistance due, in part, to a predominant glycolytic energy metabolism, which drives aggressive cancer cell proliferation. However, the characterization of these secretomes and the molecular events that associate them with acquired drug resistance remain poorly understood. In this study, we show that secretomes of cancer cells with high-level paclitaxel resistance stimulated cell proliferation and suppressed drug-induced apoptosis of drug-sensitive cells. We also found that drug (docetaxel)-stimulated induction of interferon-α (IFN-α), IFN-λ and tumor necrosis factor-α (TNF-α) release in drug-sensitive cells was lowered by these secretomes. The promotion of cell proliferation by paclitaxel-resistant (PacR) cancer cell secretomes was associated, in part, with an increase in S phase of the cell cycle and downregulation of the cell death pathway that supports escape from apoptosis. In addition, we also found that the regulation of targeted glycolysis in PacR cancer cells alters the effects of the secretomes on cell growth, apoptosis, ATP generation and acquired drug resistance. Further study revealed that the deletion of FOXO3a transcription exacerbates glycolytic shift-induced apoptosis by rescuing TRAIL expression. By generating a docetaxel–cross-resistant PacR cancer cell line (PacR/DCT), we further clarified the role of FOXO3a in glycolysis-associated mediation of P-glycoprotein/ABCB1 hyperactivity that induces docetaxel cross-resistance. These findings suggest that suppression of the cellular energy supply by targeting glycolysis may inhibit the multiplicity of acquired chemotherapy resistance. Therefore, the therapeutic inhibition of FOXO3a might direct glycolysis to induce apoptosis and overcome multidrug resistance in cancer cells. A study of molecules secreted by cancer cells reveals how they help the cells to evade anti-cancer chemotherapy. Sang Kook Lee and colleagues at Seoul National University in South Korea examined the secretions of human lung and prostate cancer cells that are resistant to the drug paclitaxel. They found that secreted molecules suppressed the cell-killing response to paclitaxel and also promoted resistance to another drug, docetaxel. These effects facilitated the survival and proliferation of the entire cancer cell population. The research also identified key aspects of the signaling pathways through which the secreted molecules work, particularly those involving a gene-controlling protein known as FOXO3a. Insights into the role of this regulatory pathway and its effect on cancer cell metabolism could aid further work to combat multi-drug resistance in cancer.