有丝分裂灾难（MC）是在有丝分裂失调的情况下发生的，代表了一种特异性根除肿瘤细胞的迷人策略。细胞焦亡是否是 MC 的一种死亡形式仍不清楚。蛋白酶体介导的蛋白质降解对于 M 期至关重要。硼替佐米 (BTZ) 可抑制蛋白酶体的 20S 催化颗粒，被批准用于治疗多发性骨髓瘤和套细胞淋巴瘤，但由于原发性耐药而不能治疗实体瘤。迄今为止，蛋白酶体抑制剂是否以及如何影响 M 期细胞的命运仍有待探索。在这里，我们表明，BTZ 治疗或沉默 PSMC5（蛋白酶体 19S 调节颗粒的亚基）会导致 G2 期和 M 期停滞、多极纺锤体形成，以及随后的 caspase-3/GSDME 介导的 M 细胞焦亡。阶段（称为有丝分裂焦亡）。进一步研究表明，WEE1/PKMYT1 抑制剂 (PD0166285) 可消除 BTZ 诱导的 G2 期停滞，从而加剧 BTZ 诱导的有丝分裂停滞和细胞焦亡，但 ATR、CHK1 或 CHK2 抑制剂则不然。 BTZ 和 PD0166285 联合治疗（称为 BP-Combo）选择性杀死各种类型的实体瘤细胞，与 BTZ 或 PD0166285 单一治疗相比，显着降低 BTZ 和 PD0166285 的 IC50。使用各种小鼠模型的研究表明，BP-Combo对肿瘤生长和转移的抑制作用比BTZ或PD0166285单药治疗强得多，并且在BP-Combo治疗的小鼠中没有观察到明显的毒性。这些发现揭示了蛋白酶体抑制剂在诱导M期焦亡中的作用，将焦亡描述为有丝分裂灾难的新死亡形式，并确定蛋白酶体和WEE家族激酶的双重抑制是一种有前景的选择性杀死实体瘤细胞的抗癌策略.© 2024。作者。

Mitotic catastrophe (MC), which occurs under dysregulated mitosis, represents a fascinating tactic to specifically eradicate tumor cells. Whether pyroptosis can be a death form of MC remains unknown. Proteasome-mediated protein degradation is crucial for M-phase. Bortezomib (BTZ), which inhibits the 20S catalytic particle of proteasome, is approved to treat multiple myeloma and mantle cell lymphoma, but not solid tumors due to primary resistance. To date, whether and how proteasome inhibitor affected the fates of cells in M-phase remains unexplored. Here, we show that BTZ treatment, or silencing of PSMC5, a subunit of 19S regulatory particle of proteasome, causes G2- and M-phase arrest, multi-polar spindle formation, and consequent caspase-3/GSDME-mediated pyroptosis in M-phase (designated as mitotic pyroptosis). Further investigations reveal that inhibitor of WEE1/PKMYT1 (PD0166285), but not inhibitor of ATR, CHK1 or CHK2, abrogates the BTZ-induced G2-phase arrest, thus exacerbates the BTZ-induced mitotic arrest and pyroptosis. Combined BTZ and PD0166285 treatment (named BP-Combo) selectively kills various types of solid tumor cells, and significantly lessens the IC50 of both BTZ and PD0166285 compared to BTZ or PD0166285 monotreatment. Studies using various mouse models show that BP-Combo has much stronger inhibition on tumor growth and metastasis than BTZ or PD0166285 monotreatment, and no obvious toxicity is observed in BP-Combo-treated mice. These findings disclose the effect of proteasome inhibitors in inducing pyroptosis in M-phase, characterize pyroptosis as a new death form of mitotic catastrophe, and identify dual inhibition of proteasome and WEE family kinases as a promising anti-cancer strategy to selectively kill solid tumor cells.© 2024. The Author(s).