JNK suppression of chemotherapeutic agents-induced ROS confers chemoresistance on pancreatic cancer stem cells.
JNK suppression of chemotherapeutic agents-induced ROS confers chemoresistance on pancreatic cancer stem cells.
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DOI：
10.18632/oncotarget.2693
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发表时间：
2015-01-01
期刊：
影响因子：
--
通讯作者：
Kitanaka C
中科院分区：
文献类型：
--
作者：
Suzuki S;Okada M;Shibuya K;Seino M;Sato A;Takeda H;Seino S;Yoshioka T;Kitanaka C
与癌症干细胞（CSC）相关的化学抗性现在被认为是胰腺癌的普遍治疗抗性的原因，这对成功管理这种毁灭性的恶性肿瘤构成了重大挑战。然而，胰腺癌干细胞显著耐药的分子机制在很大程度上仍然未知。在这里，我们发现JNK在胰腺CSC中上调并有助于其维持，其在胰腺CSC对5-氟尿嘧啶（5-FU）和吉西他滨（GEM）的抗性中起关键作用。我们发现JNK抑制有效地使另外的化学抗性胰腺CSC对5-FU和GEM敏感。显著地，JNK抑制促进了5-FU和GEM诱导的细胞内活性氧（ROS）的增加，并且通过使用N-乙酰半胱氨酸清除细胞内ROS损害了JNK抑制介导的5-FU和GEM的细胞毒性的促进。因此，我们的研究结果表明，JNK可能有助于胰腺癌干细胞的化疗耐药性，通过预防化疗药物诱导的细胞内ROS的增加。我们的研究结果还表明，JNK抑制联合5-FU和/或GEM方案可能是有效消除胰腺CSC的合理治疗方法。
Chemoresistance associated with cancer stem cells (CSCs), which is now being held responsible for the pervasive therapy resistance of pancreatic cancer, poses a major challenge to the successful management of this devastating malignancy. However, the molecular mechanism underlying the marked chemoresistance of pancreatic CSCs remains largely unknown. Here we show that JNK, which is upregulated in pancreatic CSCs and contributes to their maintenance, is critically involved in the resistance of pancreatic CSCs to 5-fluorouracil (5-FU) and gemcitabine (GEM). We found that JNK inhibition effectively sensitizes otherwise chemoresistant pancreatic CSCs to 5-FU and GEM. Significantly, JNK inhibition promoted 5-FU- and GEM-induced increase in intracellular reactive oxygen species (ROS), and scavenging intracellular ROS by use of N-acetylcysteine impaired JNK inhibition-mediated promotion of the cytotoxicity of 5-FU and GEM. Our findings thus suggest that JNK may contribute to the chemoresistance of pancreatic CSCs through prevention of chemotherapeutic agents-induced increase in intracellular ROS. Our findings also suggest that JNK inhibition combined with 5-FU- and/or GEM-based regimens may be a rational therapeutic approach to effectively eliminate pancreatic CSCs.
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影响因子：
5.2
作者：
Okada, Masashi;Sato, Atsushi;Kitanaka, Chifumi
通讯作者：
Kitanaka, Chifumi
DOI：
10.1016/j.bbamcr.2012.06.007
发表时间：
2012-10-01
影响因子：
5.1
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Mandal, Chitra
影响因子：
56.9
作者：
NICHOLS, WW;MURPHY, DG;DWIGHT, SA
通讯作者：
DWIGHT, SA
影响因子：
--
作者：
Bao, Bin;Ahmad, Aamir;Azmi, Asfar S;Ali, Shadan;Sarkar, Fazlul H
通讯作者：
Sarkar, Fazlul H