In the clinical treatment of cancer,chemotherapy often induces tumor cell senescence due to its genotoxicity.The secretion of senescence associated secretory phenotype(SASP)and the emergence of stem cell populations a...In the clinical treatment of cancer,chemotherapy often induces tumor cell senescence due to its genotoxicity.The secretion of senescence associated secretory phenotype(SASP)and the emergence of stem cell populations are important factors driving acquired resistance to chemotherapy.Direct removal of senescent tumor cells or indirect inhibition of SASP and stemness-related phenotypes are effective strategies to overcome chemoresistance.Cisplatin(CDDP),a broad-spectrum first-line chemotherapeutic agent,has been observed to induce tumor cell senescence in clinical settings,yet the properties of these senescent cells remain largely unexplored.Herein,we simulated the induction of tumor senescence using the sublethal doses of CDDP and confirmed the pivotal role of senescence in promoting chemoresistance,as well as the interdependent relationship between SASP and senescence-associated stemness.Notably,we discovered that glutaminase-1(GLS1)is highly expressed in cisplatin-induced senescent tumor cells and is intimately linked to their survival.Furthermore,we identified a natural cyclopeptide,RA-V,derived from Rubia yunnanensis,which partially eliminated senescent tumor cells,inhibited SASP secretion and stemness-related phenotypes.Mechanistically,RA-V disrupted senescent cell survival by inhibiting GLS1 protein expression through the modulation of c-Myc/GLS1 axis.Our findings reveal for the first time that GLS1 might serve as a vulnerable target in cisplatin-induced senescent tumor cells and discover the potential of RA-V as a senolytics agent,offering a promising approach to circumvent cisplatin chemoresistance.展开更多
基金supported by the grants from the National Natural Science Foundation of China(No.32070356,82474065).
文摘In the clinical treatment of cancer,chemotherapy often induces tumor cell senescence due to its genotoxicity.The secretion of senescence associated secretory phenotype(SASP)and the emergence of stem cell populations are important factors driving acquired resistance to chemotherapy.Direct removal of senescent tumor cells or indirect inhibition of SASP and stemness-related phenotypes are effective strategies to overcome chemoresistance.Cisplatin(CDDP),a broad-spectrum first-line chemotherapeutic agent,has been observed to induce tumor cell senescence in clinical settings,yet the properties of these senescent cells remain largely unexplored.Herein,we simulated the induction of tumor senescence using the sublethal doses of CDDP and confirmed the pivotal role of senescence in promoting chemoresistance,as well as the interdependent relationship between SASP and senescence-associated stemness.Notably,we discovered that glutaminase-1(GLS1)is highly expressed in cisplatin-induced senescent tumor cells and is intimately linked to their survival.Furthermore,we identified a natural cyclopeptide,RA-V,derived from Rubia yunnanensis,which partially eliminated senescent tumor cells,inhibited SASP secretion and stemness-related phenotypes.Mechanistically,RA-V disrupted senescent cell survival by inhibiting GLS1 protein expression through the modulation of c-Myc/GLS1 axis.Our findings reveal for the first time that GLS1 might serve as a vulnerable target in cisplatin-induced senescent tumor cells and discover the potential of RA-V as a senolytics agent,offering a promising approach to circumvent cisplatin chemoresistance.
