Abstract
Aberrant lipid accumulation is a hallmark of cancer known to contribute to its aggressiveness and malignancy. Emerging studies have demonstrated context-dependent changes in lipid metabolism during chemotherapy. However, there is little known regarding the mechanisms linking lipid metabolism to chemotherapy-induced cell fates. Here, we describe lipid accumulation in cells following antimitotic drug treatment. Cells arrested in mitosis, as well as cells that escaped mitotic arrest and underwent mitotic slippage, showed elevated cytoplasmic lipid droplets. Interestingly, we found that TOFA, a lipid biosynthesis inhibitor that targets acetyl-CoA carboxylase (ACC) and blocks lipid accumulation, promoted early slippage, reduced cellular stress and enhanced survival of antimitotic-treated cells. Our work previously revealed that cells that survive after mitotic slippage can become senescent and confer pro-tumourigenic effects through paracrine signalling. Modulating lipid biosynthesis in cells post slippage by TOFA amplified their inflammatory secretion profiles and accelerated the development of tumourigenic behaviour, particularly cell migration and invasion, in a paracrine-dependent manner. In contrast to TOFA, inhibition of lipid accumulation by C75, a drug targeting fatty acid synthase (FASN), significantly reduced the production of pro-tumourigenic factors and associated phenotypic effects. This suggests that discrete lipid biosynthesis pathways could contribute differentially to the regulation of pro-tumourigenic inflammation. The divergent effects of TOFA and C75 may be attributed to the opposing regulation of Malonyl-CoA, an intermediate in fatty acid synthesis that serves as a mediator of fatty acid oxidation. Taken together, our data reveal a previously unappreciated role for lipid accumulation in the cellular adaptation to antimitotic drug treatment. Targeting lipid biosynthesis in cells post slippage may reprogramme its secretory profile such that it not only negates tumour-promoting effects, but may also promote anti-tumour inflammation for clearance of post-slippage senescent cells.
Highlights
Antimitotic drugs, such as paclitaxel and vinblastine, are often used as first-line therapy against a broad range of cancers[1,2]
We have previously shown that the senescence-associated secretory phenotype (SASP) factors[7], consisting of various cytokines, chemokines and growth factors released by post-slippage senescent cells, promote tumourigenic behaviour in neighbouring cells[8]
Antimitotic drugs induce lipid accumulation during mitotic arrest and after slippage To interrogate the effects of antimitotic drugs in modulating lipid metabolism, we first treated mitotic slippageprone osteosarcoma U2OS cells with Noc and assessed lipid accumulation in these cells
Summary
Antimitotic drugs, such as paclitaxel and vinblastine, are often used as first-line therapy against a broad range of cancers[1,2]. These drugs affect cell proliferation culminating in a mitotic arrest and eventually mitotic cell death. We have previously shown that the senescence-associated secretory phenotype (SASP) factors[7], consisting of various cytokines, chemokines and growth factors released by post-slippage senescent cells, promote tumourigenic behaviour in neighbouring cells[8]. Persistence of cells post slippage may undermine the effectiveness of antimitotic drugs and contribute to the development of tumour recurrence and chemoresistance. It is crucial to gain better mechanistic understanding of the senescent cell fate post slippage for enhanced therapeutic strategies involving the elimination of senescent cells or its associated pro-tumourigenic effects post slippage following antimitotic therapy
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