Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
Int J Biol Sci. 2021 Jun 22;17(10):2606-2621. doi: 10.7150/ijbs.60292. eCollection 2021.
Cisplatin (DDP) was reported to improve pathological complete response (pCR) rates in triple-negative breast cancer (TNBC) patients, however, the molecular mechanism still remains largely unknown. Emerging evidence suggested that some chemotherapeutic drugs played anti-tumor effects by inducing cell pyroptosis. Nevertheless, whether pyroptosis contributes to the DDP-induced anti-tumor effect in TNBC remains unexploited. In the present study, NLRP3/caspase-1/GSDMD pyroptosis pathway was involved in the DDP-induced anti-tumor effect of TNBC and , providing evidence that DDP might induce pyroptosis in TNBC. Moreover, DDP activated NLRP3/caspase-1/GSDMD pyroptosis pathway by up-regulating the long non-coding RNA (lncRNA) maternally expressed gene 3 (MEG3). Furthermore, knockdown of MEG3 not only partly abolished the activation effect of DDP on NLRP3/caspase-1/GSDMD pathway-mediated pyroptosis, but also reversed the suppression of DDP on tumor growth and metastasis ability and further confirming that MEG3 may partially mediate the pyroptotic signaling upon DDP treatment. Thus, our data uncovered a novel mechanism that DDP induced pyroptosis via activation of MEG3/NLRP3/caspase-1/GSDMD pathway in TNBC to exert anti-tumor effects, which may help to develop new strategies for the therapeutic interventions in TNBC.
顺铂（DDP）被报道可提高三阴性乳腺癌（TNBC）患者的病理完全缓解（pCR）率，但分子机制仍知之甚少。新出现的证据表明，一些化疗药物通过诱导细胞焦亡发挥抗肿瘤作用。然而，焦亡是否有助于 DDP 诱导的 TNBC 抗肿瘤作用尚未得到探索。在本研究中，NLRP3/caspase-1/GSDMD 细胞焦亡途径参与了 DDP 诱导的 TNBC 的抗肿瘤作用，为 DDP 可能在 TNBC 中诱导细胞焦亡提供了证据。此外，DDP 通过上调长链非编码 RNA（lncRNA）母系表达基因 3（MEG3）激活 NLRP3/caspase-1/GSDMD 细胞焦亡途径。此外，敲低 MEG3 不仅部分消除了 DDP 对 NLRP3/caspase-1/GSDMD 途径介导的细胞焦亡的激活作用，而且逆转了 DDP 对肿瘤生长和转移能力的抑制作用，进一步证实了 MEG3 可能部分介导 DDP 处理后的细胞焦亡信号。因此，我们的数据揭示了一种新的机制，即 DDP 通过激活 MEG3/NLRP3/caspase-1/GSDMD 途径诱导 TNBC 中的细胞焦亡来发挥抗肿瘤作用，这可能有助于为 TNBC 的治疗干预制定新的策略。
