Therapeutic targeting of pancreatic cancer stem cells by dexamethasone modulation of the MKP-1-JNK axis.
Therapeutic targeting of pancreatic cancer stem cells by dexamethasone modulation of the MKP-1-JNK axis.
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DOI：
10.1074/jbc.ra120.015223
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发表时间：
2020-12-25
期刊：
影响因子：
--
通讯作者：
Kitanaka C
中科院分区：
文献类型：
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作者：
Suzuki S;Okada M;Sanomachi T;Togashi K;Seino S;Sato A;Yamamoto M;Kitanaka C
为了治愈包括胰腺癌在内的难治性癌症，必须防止显微镜下残留疾病的术后复发。这一目标的关键是消除具有肿瘤引发能力和耐药性的癌症干细胞（CSC）。然而，目前能够实现这一点的治疗策略是不够的。使用体外模型的CSC和体内模型的肿瘤起始中，CSC引起异种移植肿瘤，我们表明，地塞米松诱导MKP-1，MAPK磷酸酶的表达，通过糖皮质激素受体活化，从而灭活JNK，这是所需的自我更新和肿瘤起始的胰腺CSC以及他们的表达生存素，抗凋亡蛋白牵连多药耐药。我们还证明，全身给予临床相关剂量的地塞米松和吉西他滨可预防胰腺癌异种移植模型中CSC的肿瘤形成。因此，我们的研究为地塞米松作为辅助治疗预防胰腺癌患者术后复发的有效性提供了临床前证据。
Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer. Key to this goal is the elimination of cancer stem cells (CSCs) endowed with tumor-initiating capacity and drug resistance. However, current therapeutic strategies capable of accomplishing this are insufficient. Using in vitro models of CSCs and in vivo models of tumor initiation in which CSCs give rise to xenograft tumors, we show that dexamethasone induces expression of MKP-1, a MAPK phosphatase, via glucocorticoid receptor activation, thereby inactivating JNK, which is required for self-renewal and tumor initiation by pancreatic CSCs as well as for their expression of survivin, an anti-apoptotic protein implicated in multidrug resistance. We also demonstrate that systemic administration of clinically relevant doses of dexamethasone together with gemcitabine prevents tumor formation by CSCs in a pancreatic cancer xenograft model. Our study thus provides preclinical evidence for the efficacy of dexamethasone as an adjuvant therapy to prevent postoperative recurrence in patients with pancreatic cancer.