Persistence of drug-resistant breast cancer stem cells(brCSCs)after a chemotherapeutic regime correlates with disease recurrence and elevated mortality.Therefore,deciphering mechanisms that dictate their drug-resistan...Persistence of drug-resistant breast cancer stem cells(brCSCs)after a chemotherapeutic regime correlates with disease recurrence and elevated mortality.Therefore,deciphering mechanisms that dictate their drug-resistant phenotype is imperative for designing targeted and more effective therapeutic strategies.The transcription factor SOX2 has been recognized as a protagonist in brCSC maintenance,and previous studies have confirmed that inhibition of SOX2 purportedly eliminated these brCSCs.However,pharmacological targeting of transcription factors like SOX2 is challenging due to their structural incongruities and intrinsic disorders in their binding interfaces.Therefore,transcriptional co-activators may serve as a feasible alternative for effectively targeting the brCSCs.Incidentally,transcriptional co-activators YAP/TAZ were found to be upregulated in CD44^(+)/CD24^(-)/ALDH^(+)cells isolated from patient breast tumors and CSC-enriched mammospheres.Interestingly,it was observed that YAP/TAZ exhibited direct physical interaction with SOX2 and silencing YAP/TAZ attenuated SOX2 expression in mammospheres,leading to significantly reduced sphere forming efficiency and cell viability.YAP/TAZ additionally manipulated redox homeostasis and regulated mitochondrial dynamics by restraining the expression of the mitochondrial fission marker,DRP1.Furthermore,YAP/TAZ inhibition induced DRP1 expression and impaired OXPHOS,consequently inducing apoptosis in mammospheres.In order to enhance clinical relevance of the study,an FDA-approved drug verteporfin(VP),was used for pharmacological inhibition of YAP/TAZ.Surprisingly,VP administration was found to reduce tumor-initiating capacity of the mammospheres,concomitant with disrupted mitochondrial homeostasis and significantly reduced brCSC population.Therefore,VP holds immense potential for repurposing and decisively eliminating the chemoresistant brCSCs,offering a potent strategy for managing tumor recurrence effectively.展开更多
目的探讨核基质结合区结合蛋白,富含A-T序列特异性结合蛋白1(special A-T rich sequencebinding protein 1,SATB1)对乳腺癌干细胞表型CD44+/CD24-的影响及机制。方法用SATB1相关小干扰RNA(SATB1related small interfering RNA,SATB1-siR...目的探讨核基质结合区结合蛋白,富含A-T序列特异性结合蛋白1(special A-T rich sequencebinding protein 1,SATB1)对乳腺癌干细胞表型CD44+/CD24-的影响及机制。方法用SATB1相关小干扰RNA(SATB1related small interfering RNA,SATB1-siRNA)双链寡核糖核酸干扰MDA-MB-231细胞;pEGFP-N1-SATB1-GFP真核表达质粒瞬时转染MCF7细胞后,流式细胞术检测SATB1对乳腺癌干细胞表型CD44+/CD24-表达的影响。结果 MCF7细胞转染SATB1后,表达CD44+/CD24-的细胞比例明显升高;MDA-MB-231细胞在SATB1-siRNA干扰后,表达CD44+/CD24-的细胞比例明显降低(P<0.05)。结论 SATB1可能在形成并维持乳腺癌肿瘤干细胞特性中起重要作用。展开更多
基金supported by Department of Science and Technology and Biotechnology,GoWB,India(Sanction No.:140(Sanc.)-BT/P/Budget/RD-75/2017 dated 16.11.2018)to U.CDST-FIST,GoI for providing infrastructure support to Department of Zoology,University of Calcutta+2 种基金CSIR,GoI,for funding their fellowship(File No.09/028(1066)/2018-EMRI and 09/028(1138)/2019-EMR-I,respectively)supported by a grant from the Natural Sciences and Engineering Research Council of Canadasupported by a Queen Elizabeth Ⅱ Diamond Jubilee Scholarship and an FRQ-NT scholarship.
文摘Persistence of drug-resistant breast cancer stem cells(brCSCs)after a chemotherapeutic regime correlates with disease recurrence and elevated mortality.Therefore,deciphering mechanisms that dictate their drug-resistant phenotype is imperative for designing targeted and more effective therapeutic strategies.The transcription factor SOX2 has been recognized as a protagonist in brCSC maintenance,and previous studies have confirmed that inhibition of SOX2 purportedly eliminated these brCSCs.However,pharmacological targeting of transcription factors like SOX2 is challenging due to their structural incongruities and intrinsic disorders in their binding interfaces.Therefore,transcriptional co-activators may serve as a feasible alternative for effectively targeting the brCSCs.Incidentally,transcriptional co-activators YAP/TAZ were found to be upregulated in CD44^(+)/CD24^(-)/ALDH^(+)cells isolated from patient breast tumors and CSC-enriched mammospheres.Interestingly,it was observed that YAP/TAZ exhibited direct physical interaction with SOX2 and silencing YAP/TAZ attenuated SOX2 expression in mammospheres,leading to significantly reduced sphere forming efficiency and cell viability.YAP/TAZ additionally manipulated redox homeostasis and regulated mitochondrial dynamics by restraining the expression of the mitochondrial fission marker,DRP1.Furthermore,YAP/TAZ inhibition induced DRP1 expression and impaired OXPHOS,consequently inducing apoptosis in mammospheres.In order to enhance clinical relevance of the study,an FDA-approved drug verteporfin(VP),was used for pharmacological inhibition of YAP/TAZ.Surprisingly,VP administration was found to reduce tumor-initiating capacity of the mammospheres,concomitant with disrupted mitochondrial homeostasis and significantly reduced brCSC population.Therefore,VP holds immense potential for repurposing and decisively eliminating the chemoresistant brCSCs,offering a potent strategy for managing tumor recurrence effectively.
