Targeting the K-Ras--JNK axis eliminates cancer stem-like cells and prevents pancreatic tumor formation.
Targeting the K-Ras--JNK axis eliminates cancer stem-like cells and prevents pancreatic tumor formation.
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DOI：
10.18632/oncotarget.2087
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发表时间：
2014-07-15
期刊：
影响因子：
--
通讯作者：
Kitanaka C
中科院分区：
文献类型：
--
作者：
Okada M;Shibuya K;Sato A;Seino S;Suzuki S;Seino M;Kitanaka C
具有自我更新和启动肿瘤能力的癌细胞，无论是静止的(癌症干细胞，CSCs)还是增殖的(癌症干细胞，CSLC)，现在被认为是胰腺癌普遍耐药的原因。胰腺癌是人类最致命的癌症之一，其特点是K-Ras突变的高发。然而，到目前为止，胰腺CSCs/CSLC是如何调控的还不清楚。在此，我们发现K-RAS-JNK轴在维持胰腺CSCs/CSLCs中起着关键作用。在体外，对JNK的抑制，无论是药物上的还是遗传上的，都会导致胰腺CSLCs自我更新和致瘤能力的丧失。重要的是，通过全身应用JNK抑制剂在体内抑制JNK对小鼠的一般健康状况没有明显影响，有效地耗尽了预先建立的胰腺肿瘤移植瘤中的CSC/CSLC群体。此外，在K-RAS突变的胰腺CSLC中，K-RAS的敲除导致JNK通路下调，并丧失自我更新和启动肿瘤的能力。综上所述，我们的研究结果表明，胰腺CSCs/CSLC依赖于JNK的K-RAS激活，K-Ras-JNK轴也可能成为CSC/CSLC导向治疗胰腺癌的潜在靶点。
Cancer cells with self-renewal and tumor-initiating capacity, either quiescent (cancer stem cells, CSCs) or proliferating (cancer stem-like cells, CSLCs), are now deemed responsible for the pervasive therapy resistance of pancreatic cancer, one of the deadliest human cancers characterized by high prevalence of K-Ras mutation. However, to date, much remains unknown how pancreatic CSCs/CSLCs are regulated. Here we show that the K-Ras – JNK axis plays a pivotal role in the maintenance of pancreatic CSCs/CSLCs. In vitro inhibition of JNK, either pharmacological or genetic, caused loss of the self-renewal and tumor-initiating capacity of pancreatic CSLCs. Importantly, JNK inhibition in vivo via systemic JNK inhibitor administration, which had no discernible effect on the general health status of mice, efficiently depleted the CSC/CSLC population within pre-established pancreatic tumor xenografts. Furthermore, knockdown of K-Ras in pancreatic CSLCs with K-Ras mutation led to downregulation of the JNK pathway as well as in loss of self-renewal and tumor-initiating capacity. Together, our findings suggest that pancreatic CSCs/CSLCs are dependent on K-Ras activation of JNK and also suggest that the K-Ras – JNK axis could be a potential target in CSC/CSLC-directed therapies against pancreatic cancer.
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