Role of autophagy in regulation of glioma stem cells population during therapeutic stress
Role of autophagy in regulation of glioma stem cells population during therapeutic stress
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DOI：
10.46582/jsrm.1602012
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发表时间：
2020-01-01
影响因子：
2.7
通讯作者：
Tiwari, M.
中科院分区：
文献类型：
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作者：
Abbas, S.;Singh, S. K.;Tiwari, M.
胶质母细胞瘤是一种复发率高、侵袭性强、预后差的肿瘤，胶质瘤干细胞(GSCs)群的存在是公认的。GSCs具有自我更新、增殖和治疗耐药等干细胞特性，这些特性有助于其在肿瘤进展、转移和复发中发挥作用。肿瘤干细胞(CSCs)也可以在放化疗后从非干细胞癌细胞中诱导出来，从而进一步促进治疗后的癌症复发。自噬的作用与不同癌症中CSCs的存在有关；然而，它在GSCs中的作用仍不清楚。此外，由于自噬是由不同的化疗药物诱导的，因此了解自噬在治疗诱导的肿瘤干细胞池中的作用就变得非常重要。在这里，我们研究了自噬在维持GSCs和替莫唑胺(TMZ)诱导的治疗反应中的作用。将胶质母细胞瘤细胞系(U87 MG、LN229)培养成单层、富含GSC的肿瘤球体和亚球体细胞。我们的结果表明，与单层细胞相比，肿瘤微球保持了更高的自噬水平，抑制自噬显着降低了GSCs的比例和自我更新能力。此外，临床相关浓度的TMZ可诱导胶质母细胞瘤细胞的存活自噬。我们还观察到，TMZ治疗显著增加了GSC标志物的表达，表明GSC池增加。重要的是，抑制自噬阻止了TMZ诱导的GSC数量的增加，这表明自噬在治疗诱导的GSC池的产生中起着关键作用。总体而言，我们的发现揭示：i)GSCs中更高水平的自噬；ii)TMZ诱导保护性自噬并上调GSCs池；iii)抑制自噬阻止TMZ诱导的GSCs池，这表明它在调节GSC群体对化疗的反应中的作用。我们的研究表明自噬对GSCs存活的积极贡献，这意味着在针对TMZ诱导的GSCs的有效治疗策略的联合方法中使用自噬抑制剂。由于自噬具有广泛的治疗意义，因此需要进一步研究自噬在其他癌症类型的治疗诱导的GSC池中的作用。
Glioblastoma is highly recurrent and aggressive tumor with poor prognosis where existence of glioma stem cell (GSCs) population is well established. The GSCs display stem cell properties such as self-renewable, proliferation and therapeutic resistance which contribute to its role in tumor progression, metastasis and recurrence. Cancer stem cells (CSCs) can also be induced from non-stem cancer cells in response to radio/chemotherapy that further contribute to cancer relapse post therapy. Role of autophagy has been implicated in the existence of CSCs in different cancers; however, its role in GSCs is still unclear. Moreover, since autophagy is induced in response to various chemotherapeutic agents, it becomes imperative to understand the role of autophagy in therapy-induced pool of CSCs. Here, we investigated the role of autophagy in the maintenance of GSCs and temozolomide (TMZ)-induced therapeutic response. Glioblastoma cell lines (U87MG, LN229) were cultured as monolayer as well as GSC enriched tumorspheres and sub-spheroid population. Our results demonstrated that the tumorspheres maintained higher level of autophagy than the monolayer cells and inhibition of autophagy significantly reduced the percentage of GSCs and their self-renewal capacity. Further, TMZ at clinically relevant concentration resulted in an induction of survival autophagy in glioblastoma cells. We also observed that TMZ treatment significantly increased the expression of GSC markers, suggesting an increased pool of GSCs. Importantly, inhibition of autophagy prevented this TMZ-induced increased GSC population, suggesting a critical role for autophagy in therapy-induced generation of GSC pool. Overall, our findings revealed; i) higher levels of autophagy in GSCs; ii) TMZ induces protective autophagy and up-regulates pool of GSCs; and iii) inhibition of autophagy prevents TMZ-induced GSCs pool suggesting its role regulating GSC population in response to chemotherapy. Our study signifies a positive contribution of autophagy in survival of GSCs which implicates the use of autophagy inhibitors in a combinational approach to target TMZ-induced GSCs for developing effective therapeutic strategies. Further efforts are required to study the role of autophagy in therapy- induced GSC pool in other cancer types for its broad therapeutic implication.