Mukherjee Pritha, Bagchi Arka, Banerjee Ananya, Roy Himansu, Bhattacharya Arijit, Biswas Arunima, Chatterji Urmi
Cancer Research Laboratory, Department of Zoology, University of Calcutta, Kolkata, India.
Molecular Cell Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani, India.
J Cell Biochem. 2022 Dec;123(12):1980-1996. doi: 10.1002/jcb.30325. Epub 2022 Sep 5.
Ineffective cancer treatment is implicated in metastasis, recurrence, resistance to chemotherapy and radiotherapy, and evasion of immune surveillance. All these failures occur due to the persistence of cancer stem cells (CSCs) even after rigorous therapy, thereby rendering them as essential targets for cancer management. Contrary to the quiescent nature of CSCs, a gene profiler array disclosed that phosphatidylinositol-3-kinase (PI3K), which is known to be crucial for cell proliferation, differentiation, and survival, was significantly upregulated in CSCs. Since PI3K is modulated by cyclic adenosine 3',5' monophosphate (cAMP), analyses of cAMP regulation revealed that breast CSCs expressed increased levels of phosphodiesterase 4 (PDE4) in contrast to normal stem cells. In accordance, the effects of rolipram, a PDE4 inhibitor, were evaluated on PI3K regulators and signaling. The efficacy of rolipram was compared with paclitaxel, an anticancer drug that is ineffective in obliterating breast CSCs. Analyses of downstream signaling components revealed a switch between cell survival and death, in response to rolipram, specifically of the CSCs. Rolipram-mediated downregulation of PDE4A levels in breast CSCs led to an increase in cAMP levels and protein kinase A (PKA) expression. Subsequently, PKA-mediated upregulation of phosphatase and tensin homolog antagonized the PI3K/AKT/mTOR pathway and led to cell cycle arrest. Interestingly, direct yet noncanonical activation of mTOR by PKA, circumventing the influence of PI3K and AKT, temporally shifted the fate of CSCs toward apoptosis. Rolipram in combination with paclitaxel indicated synergistic consequences, which effectively obliterated CSCs within a tumor, thereby suggesting combinatorial therapy as a sustainable and effective strategy to abrogate breast CSCs for better patient prognosis.
无效的癌症治疗与转移、复发、化疗和放疗耐药以及免疫逃逸有关。所有这些治疗失败都是由于癌症干细胞（CSCs）即使在严格治疗后仍持续存在，因此使其成为癌症治疗的重要靶点。与CSCs的静止特性相反，基因谱阵列显示，已知对细胞增殖、分化和存活至关重要的磷脂酰肌醇-3-激酶（PI3K）在CSCs中显著上调。由于PI3K受环磷酸腺苷（cAMP）调节，对cAMP调节的分析表明，与正常干细胞相比，乳腺CSCs中磷酸二酯酶4（PDE4）的表达水平升高。相应地，评估了PDE4抑制剂咯利普兰对PI3K调节因子和信号传导的影响。将咯利普兰的疗效与紫杉醇进行了比较，紫杉醇是一种对清除乳腺CSCs无效的抗癌药物。对下游信号成分的分析揭示了细胞存活和死亡之间的转换，这是对咯利普兰的反应，特别是对CSCs的反应。咯利普兰介导的乳腺CSCs中PDE4A水平的下调导致cAMP水平和蛋白激酶A（PKA）表达增加。随后，PKA介导的磷酸酶和张力蛋白同源物的上调拮抗了PI3K/AKT/mTOR通路并导致细胞周期停滞。有趣的是，PKA对mTOR的直接而非经典激活，绕过了PI3K和AKT的影响，暂时将CSCs的命运转向凋亡。咯利普兰与紫杉醇联合使用显示出协同作用，有效地清除了肿瘤内的CSCs，从而表明联合治疗是一种可持续且有效的策略，可消除乳腺CSCs以改善患者预后。
