Signaling basis of senescence-associated secretory phenotype and its implications in epithelial ovarian cancer

项目摘要 细胞衰老是由STAND-OF-CARE等诱导剂引发的抑制肿瘤的细胞生长停滞 上皮性卵巢癌(EOC)化疗铂类药物，称为治疗性衰老。 然而，衰老细胞是有活力的，并可能通过 细胞因子、趋化因子和生长因子等因子的分泌，称为衰老 相关分泌表型(SASP)。因此，有选择地消除有害的 同时维持衰老相关的生长停滞。开发新的治疗方法 克服治疗耐药性的策略仍然是对抗EoC需要克服的主要障碍。因此， 这项提案的总体目标是调查SASP的基础机制并利用这些 为发展以衰老为基础的EoC联合疗法提供了新的机制见解。CGAS 通过识别衰老过程中的细胞质染色质片段(CCF)来促进SASP。我们的 初步研究表明，硫氧还蛋白还原酶1(TXNRD1)定位于CCF和 TXNRD1抑制损害cGAS在CCF、cGAS-STING通路和SASP中的定位 在铂诱导的EoC衰老过程中。值得注意的是，抑制TXNRD1不会影响衰老- 相关的增长停滞。本申请的目标是调查信令基础，通过它 TXNRD1控制SASP并探索以衰老为基础的EOC联合疗法 策略。我们的中心假设是TXNRD1通过促进治疗复发和耐药 SASP通过在治疗诱导的EoC衰老过程中激活cGAS-STING信号通路。 因此，我们提出了两个具体的目标：目标1是阐明分子机制。 TXNRD1在衰老过程中调节SASP，Aim 2将确定TXNRD1在EoC中的作用 治疗反应。拟议的研究具有高度的新颖性，因为这是第一次探索 通过CCF调节cGAS-STING信号通路来控制SASP的分子开关。因此， 我们的研究正在改变他们阐明SASP调控的分子基础的潜力 在衰老过程中。提出的这项研究具有很大的影响，因为它将为 通过限制SASP相关治疗，最终迫切开发新的EOC治疗策略 故态复萌和抵抗。因此，目前的研究不仅将为 SASP在衰老过程中的调控，但也将对 以衰老为基础的治疗策略。

Project Summary Cellular senescence is a tumor-suppressive cell growth arrest triggered by inducers such as stand-of-care epithelial ovarian cancer (EOC) chemotherapeutic platinum, known as therapy-induced senescence. However, senescent cells are viable and may promote therapy relapse and immune escape through the secretion of factors such as cytokines, chemokines, and growth factors, termed the senescence- associated secretory phenotype (SASP). Thus, it would be ideal to selectively eliminate the detrimental SASP while maintaining the senescence-associated growth arrest. Developing novel therapeutic strategies to overcome therapy resistance remains a major obstacle to overcome in combating EOC. Thus, the overall goal of this proposal is to investigate the mechanism underlying the SASP and leverage these newly gained mechanistic insights to develop senescence based combinatory EOC therapeutics. cGAS promotes the SASP through recognizing cytoplasmic chromatin fragments (CCF) during senescence. Our preliminary studies show that the protein Thioredoxin Reductase 1 (TXNRD1) is localized to CCF and TXNRD1 inhibition impairs the localization of cGAS into CCF, the cGAS-STING pathway, and the SASP during platinum-induced senescence in EOC. Notably, TXNRD1 inhibition does not affect senescence- associated growth arrest. The objectives of this application are to investigate the signaling basis by which TXNRD1 controls the SASP and to investigate a combination senescence based EOC therapeutic strategy. Our central hypothesis is that TXNRD1 promotes therapy relapse and resistance through the SASP by activating the cGAS-STING signaling pathway during therapy-induced senescence in EOC. Accordingly, two specific aims are proposed: Aim 1 is to elucidate the molecular mechanism by which TXNRD1 regulates the SASP during senescence, and Aim 2 will determine the role of TXNRD1 in EOC therapy response. The proposed studies are highly novel because this is the first study to explore a molecular switch that controls the SASP by regulating the cGAS-STING signaling pathway via CCF. Thus, our studies are paradigm-shifting in their potential to elucidate the molecular basis of SASP regulation during senescence. The research proposed is of high impact because it will lay the critical foundation for ultimately developing urgently novel EOC therapeutic strategies through limiting SASP-associated therapy relapse and resistance. Therefore, the current study will not only provide critical mechanistic insights into SASP regulation during senescence but will also have far-reaching implications for the development of senescence-based therapeutic strategies.