Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990-9585, Japan.
Oncol Rep. 2013 Oct;30(4):1957-64. doi: 10.3892/or.2013.2655. Epub 2013 Aug 2.
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.
现在越来越多的研究报告表明，c-Jun NH2-末端激酶（JNK）信号的失调存在于多种人类恶性肿瘤中。非小细胞肺癌（NSCLC）就是其中一种存在 JNK 异常激活的人类恶性肿瘤；然而，JNK 失调在 NSCLC 生物学中的确切作用（特别是在体内）仍不清楚。在这里，我们证明了 JNK 在控制源自人肺腺癌（NSCLC 的主要亚型之一）的 A549 细胞的肿瘤起始能力中的特定作用。尽管 SP600125 是一种可逆的 JNK 抑制剂，在体外对 A549 细胞的生长具有很强的抑制活性，但当全身给予时，它未能抑制预先建立的 A549 异种移植物在体内的生长。然而，相同的 SP600125 处理导致 A549 肿瘤内的肿瘤起始群体明显减少，这表明 JNK 可能在体内特异性地需要维持肿瘤细胞的肿瘤起始群体，而不是增殖和整个细胞群体的存活。此外，A549 细胞无论是体外先用 SP600125 预处理还是瞬时转染针对 JNK 基因的 siRNAs，在植入裸鼠后起始肿瘤形成的能力都大大降低，这意味着 A549 细胞的细胞内在 JNK 活性对于维持其肿瘤起始能力是必不可少的。据我们所知，这是第一个证明 JNK 参与控制 NSCLC 细胞的肿瘤起始能力的研究。我们的发现还提出了一个有趣的可能性，即针对 JNK 的治疗方法可能通过消除肿瘤起始细胞来有助于预防 NSCLC 的复发和/或转移。
