Sonic hedgehog signaling inhibition provides opportunities for targeted therapy by sulforaphane in regulating pancreatic cancer stem cell self-renewal.
Sonic hedgehog signaling inhibition provides opportunities for targeted therapy by sulforaphane in regulating pancreatic cancer stem cell self-renewal.
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DOI：
10.1371/journal.pone.0046083
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Shankar S
中科院分区：
文献类型：
--
作者：
Rodova M;Fu J;Watkins DN;Srivastava RK;Shankar S
Sonic Hedgehog(Shh)信号通路的失调与肿瘤干细胞(CSC)相关，并与胰腺癌的发生有关。胰腺CSCs是一种罕见的肿瘤细胞，具有自我更新的能力，是导致肿瘤复发并对现有治疗方法产生抵抗的原因。这些无法治愈的、侵袭性和侵袭性胰腺肿瘤的致命性仍然是一个令人望而生畏的临床挑战。因此，本研究的目的是研究Shh通路在胰腺癌中的作用，并探讨十字花科蔬菜中的活性物质萝卜硫素(SFN)抑制人胰腺CSCs自我更新能力的分子机制。有趣的是，我们在这里证明了Shh通路在胰腺CSCs中高度激活，并通过调节干性基因的表达在维持干性方面发挥重要作用。鉴于胰腺癌对Hedgehog的需求，我们研究了SFN对Hedgehog的阻断是否可以靶向胰腺癌的干细胞群。在体外模型中，SFN对人胰腺CSCs来源的球体有明显的抑制作用，提示CSCs的克隆性耗竭。有趣的是，SFN抑制Shh途径的组成部分和Gli的转录活性。干扰Shh-Gli信号显着阻断SFN诱导的抑制效应，表明胰腺CSCs的生长需要一条激活的途径。SFN还通过抑制多能性维持因子(Nanog和Oct-4)以及PDGFRα和Cyclin D1的表达来抑制Gli转录的下游靶点。此外，SFN通过抑制bcl-2和激活caspase诱导细胞凋亡。我们的数据揭示了Shh-Gli信号在控制胰腺CSCs特性中的重要作用。我们认为三七总皂苷的胰腺癌预防作用可能是通过抑制Shh途径实现的。因此，萝卜硫素有可能成为治疗胰腺癌的一种廉价、安全和有效的选择。
Dysregulation of the sonic hedgehog (Shh) signaling pathway has been associated with cancer stem cells (CSC) and implicated in the initiation of pancreatic cancer. Pancreatic CSCs are rare tumor cells characterized by their ability to self-renew, and are responsible for tumor recurrence accompanied by resistance to current therapies. The lethality of these incurable, aggressive and invasive pancreatic tumors remains a daunting clinical challenge. Thus, the objective of this study was to investigate the role of Shh pathway in pancreatic cancer and to examine the molecular mechanisms by which sulforaphane (SFN), an active compound in cruciferous vegetables, inhibits self-renewal capacity of human pancreatic CSCs. Interestingly, we demonstrate here that Shh pathway is highly activated in pancreatic CSCs and plays important role in maintaining stemness by regulating the expression of stemness genes. Given the requirement for Hedgehog in pancreatic cancer, we investigated whether hedgehog blockade by SFN could target the stem cell population in pancreatic cancer. In an in vitro model, human pancreatic CSCs derived spheres were significantly inhibited on treatment with SFN, suggesting the clonogenic depletion of the CSCs. Interestingly, SFN inhibited the components of Shh pathway and Gli transcriptional activity. Interference of Shh-Gli signaling significantly blocked SFN-induced inhibitory effects demonstrating the requirement of an active pathway for the growth of pancreatic CSCs. SFN also inhibited downstream targets of Gli transcription by suppressing the expression of pluripotency maintaining factors (Nanog and Oct-4) as well as PDGFRα and Cyclin D1. Furthermore, SFN induced apoptosis by inhibition of BCL-2 and activation of caspases. Our data reveal the essential role of Shh-Gli signaling in controlling the characteristics of pancreatic CSCs. We propose that pancreatic cancer preventative effects of SFN may result from inhibition of the Shh pathway. Thus Sulforaphane potentially represents an inexpensive, safe and effective alternative for the management of pancreatic cancer.
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影响因子：
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通讯作者：
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