The KEAP1/NRF2 pathway is a master regulator of several redox-sensitive genes implicated in the resistance of tumor cells against therapeutic drugs. The dysfunction of the KEAP1/NRF2 system has been correlated with neoplastic patients’ outcomes and responses to conventional therapies. In lung tumors, the growth and the progression of cancer cells may also involve the intersection between the molecular NRF2/KEAP1 axis and other pathways, including NOTCH, with implications for antioxidant protection, survival of cancer cells, and drug resistance to therapies. At present, the data concerning the mechanism of aberrant NRF2/NOTCH crosstalk as well as its genetic and epigenetic basis in SCLC are incomplete. To better clarify this point and elucidate the contribution of NRF2/NOTCH crosstalk deregulation in tumorigenesis of SCLC, we investigated genetic and epigenetic dysfunctions of theKEAP1gene in a subset of SCLC cell lines. Moreover, we assessed its impact on SCLC cells’ response to conventional chemotherapies (etoposide, cisplatin, and their combination) and NOTCH inhibitor treatments using DAPT, a γ-secretase inhibitor (GSI). We demonstrated that the KEAP1/NRF2 axis is epigenetically controlled in SCLC cell lines and that silencing ofKEAP1by siRNA induced the upregulation of NRF2 with a consequent increase in SCLC cells’ chemoresistance under cisplatin and etoposide treatment. Moreover,KEAP1modulation also interfered with NOTCH1, HES1, and DLL3 transcription. Our preliminary data provide new insights about the downstream effects of KEAP1 dysfunction on NRF2 and NOTCH deregulation in this type of tumor and corroborate the hypothesis of a cooperation of these two pathways in the tumorigenesis of SCLC.
KEAP1/NRF2通路是调控多个氧化还原敏感基因的关键途径，这些基因与肿瘤细胞对治疗药物的耐药性密切相关。KEAP1/NRF2系统的功能失调与肿瘤患者的预后及对常规治疗的反应存在关联。在肺部肿瘤中，癌细胞的生长与进展可能涉及NRF2/KEAP1分子轴与其他通路（包括NOTCH通路）的交互作用，这种相互作用对抗氧化保护、癌细胞存活及治疗耐药性具有重要影响。目前，关于小细胞肺癌中异常NRF2/NOTCH串扰机制及其遗传与表观遗传基础的研究尚不完善。为深入阐明这一问题，揭示NRF2/NOTCH串扰失调在小细胞肺癌发生发展中的作用，我们在一组小细胞肺癌细胞系中研究了KEAP1基因的遗传及表观遗传异常。此外，通过使用γ-分泌酶抑制剂DAPT，我们评估了该基因对SCLC细胞响应常规化疗（依托泊苷、顺铂及其联合用药）及NOTCH抑制剂治疗的影响。研究证实，KEAP1/NRF2轴在SCLC细胞系中受表观遗传调控，通过siRNA沉默KEAP1可诱导NRF2上调，进而增强SCLC细胞在顺铂和依托泊苷治疗下的化疗耐药性。同时，KEAP1的调控还会干扰NOTCH1、HES1和DLL3的转录。我们的初步数据为KEAP1功能失调对该类肿瘤中NRF2与NOTCH通路异常的下游效应提供了新见解，并进一步支持了这两种通路在小细胞肺癌发生过程中存在协同作用的假说。
Effects ofKEAP1Silencing on NRF2 and NOTCH Pathways in SCLC Cell Lines
肿瘤(癌症)患者之家