Autophagy Governs Protumorigenic Effects of Mitotic Slippage–induced Senescence

Abstract

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. .

Suppression of autophagy during mitosis via CUL4-RING ubiquitin ligases-mediated WIPI2 polyubiquitination and proteasomal degradation

“…Our findings are indeed consistent with an earlier report in which autophagy mediates the mitotic senescence transition and deletion of ATG5 or ATG7 led to delayed senescence transition [71]. Our findings are also consistent with a recent study demonstrating that autophagy induction during mitotic slippage is required for senescence and deletion of ATG5 led to suppression of senescence post mitotic slippage [66].…”

“…Notably, this effect was largely mitigated upon WIPI2 depletion (Figure 7(i-k)) or by inhibition of autophagy via treatment of Wortmannin ( Figure S7 (d-g)), suggesting that MLN4924-mediated senescence in the nocodazole-treated cells is regulated in a WIPI2autophagy-dependent manner. These results are consistent with a recent study demonstrating that autophagy induction during mitotic slippage is required for senescence [66].…”

An mTORC1-to-CDK1 Switch Maintains Autophagy Suppression during Mitosis

“…HCT116 cells treated with paclitaxel exhibited a time-dependent reduction in electrophoretic mobility (a surrogate for phosphorylation) of all ARs; the appearance of the phosphorylated forms correlated with the appearance of the mitotic marker phospho-S10 H3 ( Figure 3A). All ARs were hypophosphorylated again after 24 h of paclitaxel treatment, reflecting HCT116 cells undergoing mitotic slippage as evidenced by a decrease in p-S10 (H3) ( Figure 3A phagy is activated during mitotic catastrophe (Sorokina et al, 2017) or slippage (Jakhar et al, 2018;Veldhoen et al, 2013), and this may explain the discrepancy between the 16-h (mitotic) and 24-h (slippage) samples ( Figure 3A). When we immunoprecipitated ATG13 and TFEB from high-expressing cell lines (HeLa and COLO205) and treated them with lambda phosphatase, the paclitaxel-induced mobility shift was completely reversed, indicating that it did indeed reflect mitotic phosphorylation ( Figures 3B and 3C).…”

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…174,175 In fact, cancer cells may actively reprogram autophagy in stromal cells to promote cancer progression. 178 Therefore, both impaired autophagy and excessive or dysregulated autophagy can disrupt tissue homeostasis and favor cancer progression (Fig. This escape is linked to the induction of autophagy and leads to cellular senescence, migration, invasion and vascularization.…”

“…This escape is linked to the induction of autophagy and leads to cellular senescence, migration, invasion and vascularization. 178 Therefore, both impaired autophagy and excessive or dysregulated autophagy can disrupt tissue homeostasis and favor cancer progression (Fig. 4).…”