Abstract：
Frequent recurrence and metastasis caused by cancer stem cells (CSCs) are major challenges in lung cancer treatment. Therefore, identifying and characterizing specific CSC targets are crucial for the success of prospective targeted therapies. In this study, it is found that upregulated TOR Signaling Pathway Regulator-Like (TIPRL) in lung CSCs causes sustained activation of the calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) signaling pathway by binding to CaMKK2, thereby maintaining stemness and survival. CaMKK2-mediated activation of CaM kinase 4 (CaMK4) leads to phosphorylation of cAMP response element-binding protein (CREB) at Ser129 and Ser133, which is necessary for its maximum activation and the downstream constitutive expression of its target genes (Bcl2 and HMG20A). TIPRL depletion sensitizes lung CSCs to afatinib-induced cell death and reduces distal metastasis of lung cancer in vivo. It is determined that CREB activates the transcription of TIPRL in lung CSCs. The positive feedback loop consisting of CREB and TIPRL induces the sustained activation of the CaMKK2-CaMK4-CREB axis as a driving force and upregulates the expression of stemness- and survival-related genes, promoting tumorigenesis in patients with lung cancer. Thus, TIPRL and the CaMKK2 signaling axis may be promising targets for overcoming drug resistance and reducing metastasis in lung cancer.
摘要：
肿瘤干细胞（CSC）引起的频繁复发和转移是肺癌治疗的主要挑战。因此,确定和表征特定CSC靶标对于前瞻性靶向治疗的成功至关重要.在这项研究中,发现肺CSC中上调的TOR信号通路调节因子样（TIPRL）通过与CaMKK2结合，导致钙/钙调蛋白依赖性蛋白激酶激酶2（CaMKK2）信号通路的持续激活，从而维持干细胞和存活。CaMKK2介导的CaM激酶4（CaMK4）的激活导致cAMP反应元件结合蛋白（CREB）在Ser129和Ser133处的磷酸化，这对于其最大激活和其靶基因（Bcl2和HMG20A）的下游组成型表达是必需的。TIPRL耗竭使肺CSC对阿法替尼诱导的细胞死亡敏感，并减少体内肺癌的远端转移。确定CREB激活肺CSC中TIPRL的转录。由CREB和TIPRL组成的正反馈回路诱导作为驱动力的CaMKK2-CaMK4-CREB轴的持续激活，并上调干细胞和存活相关基因的表达，促进肺癌患者的肿瘤发生。因此，TIPRL和CaMKK2信号轴可能是克服肺癌耐药性和减少转移的有希望的靶标。
