Synergistic induction of mitotic pyroptosis and tumor remission by inhibiting proteasome and WEE family kinases

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.

Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis

Aberrant activation of the TGF-β/SMAD signaling pathway is often observed in hepatocellular carcinoma(HCC).Whether lncRNA regulates the TGF-β/SMAD signaling remains largely unknown.Here,we identified an oncogenic lncRNA that was upregulated in HCC and was transcriptionally induced by TGF-β(named lnc-UTGF,lncRNA upregulated by TGF-β).Upon TGF-βstimulation,SMAD2/3 bound to the lnc-UTGF promoter and activated lnc-UTGF expression.In turn,the TGF-β/SMAD signaling was augmented by overexpressing lnc-UTGF,but was inhibited by silencing lnc-UTGF.Mechanism investigations revealed that lnc-UTGF interacted with the mRNAs of SMAD2 and SMAD4 via complementary base-pairing,resulting in enhanced stability of SMAD2/4 mRNAs.These data suggest a novel TGF-β/SMAD/lnc-UTGF positive feedback circuitry.Subsequent gain-and loss-of-function analyses disclosed that lnc-UTGF promoted the migration and invasion of hepatoma cells,and this effect of lnc-UTGF was attenuated by repressing SMAD2/4 expression or by mutating the SMAD2/4-binding sites in lnc-UTGF.Studies using mouse models further confirmed that in vivo metastasis of hepatoma xenografts was inhibited by silencing lnc-UTGF,but was enhanced by ectopic expression of lncUTGF.The lnc-UTGF level was positively correlated with the SMAD2/4 levels in xenografts.Consistently,we detected an association of lnc-UTGF upregulation with increase of SMAD2,SMAD4,and their metastasis effector SNAIL1 in human HCC.And high lnc-UTGF level was also significantly associated with enhanced metastasis potential,advanced TNM stages,and worse recurrence-free survival.Conclusion:there exists a lnc-UTGF-mediated positive feedback loop of the TGF-βsignaling and its deregulation promotes hepatoma metastasis.These findings may provide a new therapeutic target for HCC metastasis.

Correction: Identification of a TGF-β/SMAD/lnc-UTGF positive feedback loop and its role in hepatoma metastasis

Correction to:Signal Transduction and Targeted Therapy https://doi.org/10.1038/s41392-021-00781-3,published online 17 November 2021 In this article^(1) Jian-Hong Fang should have been denoted as a corresponding author along with Shi-Mei Zhuang,but was inadvertently removed during the production process.The original article has been corrected.