Inactivation of TFEB and NF-kappa B by marchantin M alleviates the chemotherapy-driven protumorigenic senescent secretion
Inactivation of TFEB and NF-kappa B by marchantin M alleviates the chemotherapy-driven protumorigenic senescent secretion
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Marchantin M 灭活 TFEB 和 NF-κ B 可减轻化疗驱动的促肿瘤衰老分泌
DOI：
10.1016/j.apsb.2019.08.007
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发表时间：
2019
影响因子：
14.5
通讯作者：
Yuan Huiqing
中科院分区：
文献类型：
--
作者：
Niu Huanmin;Qian Lilin;Sun Bin;Liu Wenjian;Wang Fang;Wang Qian;Ji Xiaotian;Luo Yanhai;Nesa Effat Un;Lou Hongxiang;Yuan Huiqing
衰老相关分泌表型（SASP）的调控是肿瘤治疗的关键，因为它能促进肿瘤恶性表型的发生并限制肿瘤治疗的有效性。在这项研究中，我们证明了marchantin M（Mar-M，一种天然存在的bisbibenzyl）抑制了在化疗耐药细胞中升高的促炎SASP组分。Mar-M治疗减弱了SASP的促肿瘤发生作用，并提高了耐药小鼠模型的存活率。在正常成纤维细胞上或在该处理后的动物中未检测到毒性。Mar-M对转录因子EB（TFE B）和核因子-κB（NF-κB）的失活是其抑制SASP组分的重要原因。此外，Mar-M对SASP的抑制有助于在与多柔比星共同治疗期间的协同效应，以降低毒性并增强抗肿瘤功效。因此，化疗驱动的促炎活性，被认为有助于耐药性，是Mar-M的重要靶点。通过降低SASP，Mar-M可能是克服肿瘤恶性的潜在方法。
It is critical to regulate the senescence-associated secretory phenotype (SASP) due to its effect on promoting malignant phenotypes and limiting the efficiency of cancer therapy. In this study, we demonstrated that marchantin M (Mar-M, a naturally occurring bisbibenzyl) suppressed pro-inflammatory SASP components which were elevated in chemotherapy-resistant cells. Mar-M treatment attenuated the pro-tumorigenic effects of SASP and enhanced survival in drug-resistant mouse models. No toxicity was detected on normal fibroblast cells or in animals following this treatment. Inactivation of transcription factor EB (TFEB) and nuclear factor-κB (NF-κB) by Mar-M significantly accounted for its suppression on the components of SASP. Furthermore, inhibition of SASP by Mar-M contributed to a synergistic effect during co-treatment with doxorubicin to lower toxicity and enhance antitumor efficacy. Thus, chemotherapy-driven pro-inflammatory activity, seen to contribute to drug-resistance, is an important target for Mar-M. By decreasing SASP, Mar-M may be a potential approach to overcome tumor malignancy.