Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells
Specific role of JNK in the maintenance of the tumor-initiating capacity of A549 human non-small cell lung cancer cells
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DOI：
10.3892/or.2013.2655
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发表时间：
2013-10-01
期刊：
影响因子：
4.2
通讯作者：
Kitanaka, Chifumi
中科院分区：
文献类型：
--
作者：
Okada, Masashi;Shibuya, Keita;Kitanaka, Chifumi
现在越来越多地报道在各种人类恶性肿瘤中 c-Jun NH2 末端激酶 (JNK) 信号传导失调。非小细胞肺癌 (NSCLC) 属于 JNK 激活异常的人类恶性肿瘤之一。然而，JNK 失调在 NSCLC 生物学（特别是体内）中的确切作用仍不清楚。在这里，我们证明了 JNK 在控制源自人肺腺癌（NSCLC 的一种主要亚型）的 A549 细胞的肿瘤启动能力中的特定作用。尽管 SP600125（一种可逆 JNK 抑制剂）在体外对 A549 细胞生长具有有效的抑制活性，但当全身给药时，它无法抑制体内预先建立的 A549 异种移植物的生长。然而，相同的 SP600125 治疗导致 A549 肿瘤内的肿瘤起始群体显着减少，这表明 JNK 可能是体内维持肿瘤细胞的肿瘤起始群体而不是整个细胞群体的增殖和存活所特别需要的。此外，用 SP600125 预处理或用针对 JNK 基因的 siRNA 瞬时转染的 A549 细胞在体外显示在植入裸鼠后启动肿瘤形成的能力显着降低，这意味着 A549 细胞的细胞内在 JNK 活性对于维持其肿瘤启动能力至关重要。据我们所知，这是 JNK 参与控制 NSCLC 细胞肿瘤启动能力的首次证明。我们的研究结果还提出了一种有趣的可能性，即针对 JNK 的疗法可能通过消除肿瘤起始细胞来预防 NSCLC 的复发和/或转移。
Deregulation of c-Jun NH2-terminal kinase (JNK) signaling is now increasingly reported in a variety of human malignancies. Non-small cell lung cancer (NSCLC) is among such human malignancies with aberrant JNK activation; yet the exact role(s) of JNK deregulation in NSCLC biology, in particular in vivo, remains unclear. Here, we demonstrated a specific role of JNK in the control of the tumor-initiating capacity of A549 cells derived from human lung adenocarcinoma, a major subtype of NSCLC. Despite its potent inhibitory activity on A549 cell growth in vitro, SP600125, a reversible JNK inhibitor, failed to inhibit the growth of pre-established A549 xenografts in vivo when systemically administered. Nevertheless, the same SP600125 treatment caused a marked reduction in the tumor-initiating population within the A549 tumors, suggesting that JNK may be specifically required in vivo for the maintenance of the tumor-initiating population of tumor cells rather than for proliferation and survival of the entire cell population. Furthermore, A549 cells either pre-treated with SP600125 or transiently transfected with siRNAs against the JNK genes in vitro showed substantially reduced ability to initiate tumor formation upon implantation into nude mice, implying that the cell intrinsic JNK activity of A549 cells is essential for the maintenance of their tumor-initiating capacity. To our knowledge, this is the first demonstration that JNK is involved in the control of the tumor-initiating capacity of NSCLC cells. Our findings also give rise to an intriguing possibility that therapies targeting JNK could contribute to prevention of relapse and/or metastasis of NSCLC through elimination of tumor-initiating cells.