Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype
Role of nitric oxide in pancreatic cancer cells exhibiting the invasive phenotype
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DOI：
10.1016/j.redox.2019.101158
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发表时间：
2019-04-01
期刊：
影响因子：
11.4
通讯作者：
Wink, David A.
中科院分区：
文献类型：
--
作者：
Fujita, Mayumi;Somasundaram, Veena;Wink, David A.
胰腺癌是一种高度转移的肿瘤，5年生存率极低。缺乏有效的诊断和缺乏有效的治疗方法，可以针对癌症以及微环境利基是治疗和管理这种疾病的有限成功的原因。细胞通过细胞外基质（ECM）侵袭涉及细胞外基质粘附和脱离的复杂调控，对其理解对胰腺癌转移潜力至关重要。为了了解这些癌细胞的特征及其转移能力，我们比较了从transwell插入物中收集的人胰腺癌细胞系PANC-1及其入侵表型（INV）。与全细胞培养（正常培养皿培养）的PANC-1 （WCC）相比，侵袭细胞类型INV对碳离子辐射表现出更高的抗性，并且具有更有效的体外球形形成能力。一氧化氮合酶（NOS）抑制剂可抑制INV的侵袭，提示一氧化氮（NO）在PANC-1侵袭中起主要作用。此外，体外研究表明，NOS/NO调节PANC-1侵袭的机制依赖于mek - erk，不依赖于JAK。暂停INV显示NO的产生增加，并诱导了几个原转移性基因和干细胞相关基因。NOS抑制剂L-NAME可降低这些促转移或干细胞相关基因的表达，并抑制球体形成能力，提示NO可能影响胰腺癌的侵袭性。此外，在NSG小鼠模型中使用INV和WCC的异种移植研究显示，与WCC相比，INV更有能力转移到肝脏，L-NAME减少了注射INV的小鼠的转移灶。总的来说，数据表明NO是胰腺癌耐辐射和转移的关键因素；在动物模型中观察到，通过特异性靶向具有干细胞样特征并可能导致复发的转移细胞，抑制NOS显示出治疗潜力。
Pancreatic cancer is a highly metastatic tumor with an extremely low 5-year survival rate. Lack of efficient diagnostics and dearth of effective therapeutics that can target the cancer as well as the microenvironment niche are the reasons for limited success in treatment and management of this disease. Cell invasion through extracellular matrix (ECM) involves the complex regulation of adhesion to and detachment from ECM and its understanding is critical to metastatic potential of pancreatic cancer. To understand the characteristics of these cancer cells and their ability to metastasize, we compared human pancreatic cancer cell line, PANC-1 and its invading phenotype (INV) collected from transwell inserts. The invasive cell type, INV, exhibited higher resistance to Carbon-ion radiation compared to whole cultured (normally dish-cultured) PANC-1 (WCC), and had more efficient in vitro spheroid formation capability. Invasiveness of INV was hampered by nitric oxide synthase (NOS) inhibitors, suggesting that nitric oxide (NO) plays a cardinal role in PANC-1 invasion. In addition, in vitro studies indicated that a MEK-ERK-dependent, JAK independent mechanism through which NOS/NO modulate PANC-1 invasiveness. Suspended INV showed enhanced NO production as well as induction of several prometastatic, and stemness-related genes. NOS inhibitor, L-NAME, reduced the expression of these pro-metastatic or stemness-related genes, and dampened spheroid formation ability, suggesting that NO can potentially influence pancreatic cancer aggressiveness. Furthermore, xenograft studies with INV and WCC in NSG mouse model revealed a greater ability of INV compared to WCC, to metastasize to the liver and L-NAME diminished the metastatic lesions in mice injected with INV. Overall, data suggest that NO is a key player associated with resistance to radiation and metastasis of pancreatic cancer; and inhibition of NOS demonstrates therapeutic potential as observed in the animal model by specifically targeting the metastatic cells that harbor stem-like features and are potentially responsible for relapse.