The most commonly utilized class of chemotherapeutic agents administered as a first-line therapy are antimitotic drugs; however, their clinical success is often impeded by chemoresistance and disease relapse. Hence, a better understanding of the cellular pathways underlying escape from cell death is critical. Mitotic slippage describes the cellular process where cells exit antimitotic drug-enforced mitotic arrest and "slip" into interphase without proper chromosome segregation and cytokinesis. The current report explores the cell fate consequence following mitotic slippage and assesses a major outcome following treatment with many chemotherapies, therapy-induced senescence. It was found that cells postslippage entered senescence and could impart the senescence-associated secretory phenotype (SASP). SASP factor production elicited paracrine protumorigenic effects, such as migration, invasion, and vascularization. Both senescence and SASP factor development were found to be dependent on autophagy. Autophagy induction during mitotic slippage involved the autophagy activator AMPK and endoplasmic reticulum stress response protein PERK. Pharmacologic inhibition of autophagy or silencing of autophagy-related ATG5 led to a bypass of G arrest senescence, reduced SASP-associated paracrine tumorigenic effects, and increased DNA damage after S-phase entry with a concomitant increase in apoptosis. Consistent with this, the autophagy inhibitor chloroquine and microtubule-stabilizing drug paclitaxel synergistically inhibited tumor growth in mice. Sensitivity to this combinatorial treatment was dependent on p53 status, an important factor to consider before treatment. Clinical regimens targeting senescence and SASP could provide a potential effective combinatorial strategy with antimitotic drugs. .

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.

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Summary TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) plays critical roles in B cells by promoting immunoglobulin class switching and plasma cell survival. However, its expression and function in T cells remain controversial. We show here that TACI expression can be strongly induced in murine CD4 + T cells in vitro by cytokines responsible for T H 17 but not T H 1 or T H 2 differentiation. Frequencies and numbers of T H 17 cells were elevated in TACI −/ − compared with wild-type mice as well as among TACI −/ − versus wild-type CD4 + T cells in mixed bone marrow chimeras, arguing for a T cell-intrinsic effect in the contribution of TACI deficiency to T H 17 cell accumulation. TACI −/ − mice were more susceptible to severe colitis induced by dextran sodium sulfate or adoptive T cell transfer, suggesting that TACI negatively regulates T H 17 function and limits intestinal inflammation in a cell-autonomous manner. Finally, transcriptomic and biochemical analyses revealed that TACI −/ − CD4 + T cells exhibited enhanced activation of T H 17-promoting transcription factors NFAT, IRF4, c-MAF, and JUNB. Taken together, these findings reveal an important role of TACI in constraining T H 17 pathogenicity and protecting against gut disease.