Curtin James F, Cotter Thomas G
Tumour Biology Laboratory, Department of Biochemistry, Biosciences Research Institute, University College Cork, Cork, Ireland.
J Biol Chem. 2004 Apr 23;279(17):17090-100. doi: 10.1074/jbc.M307629200. Epub 2004 Feb 6.
Elevated endogenous JNK activity and resistance to Fas receptor-mediated apoptosis have recently been implicated in progression of prostate cancer and can promote resistance to apoptosis in response to chemotherapeutic drugs. In addition, JNK has been demonstrated to promote transformation of epithelial cells by increasing both proliferation and survival. Although numerous studies have reported a role for JNK in promoting Fas receptor-mediated apoptosis, there is a paucity in the literature studying the antiapoptotic function of JNK during Fas receptor-mediated apoptosis. Consequently, we have used the recently described specific JNK inhibitor SP600125 and RNA interference to inhibit endogenous JNK activity in the prostate carcinoma cell line DU 145. We demonstrated that endogenous JNK activity increased the expression of a kinase, HIPK3, that has previously been implicated in multidrug resistance in a number of tumors. HIPK3 has also been reported to phosphorylate FADD. The interaction between FADD and caspase-8 was inhibited, but abrogation of JNK activity or HIPK3 expression was found to restore this interaction and increased the sensitivity of DU 145 cells to Fas receptor-mediated apoptosis. In conclusion, we present novel evidence that JNK regulates the expression of HIPK3 in prostate cancer cells, and this contributes to increased resistance to Fas receptor-mediated apoptosis by reducing the interaction between FADD and caspase-8.
内源性JNK活性升高以及对Fas受体介导的凋亡产生抗性，最近被认为与前列腺癌的进展有关，并且会促进对化疗药物诱导的凋亡产生抗性。此外，JNK已被证明可通过增加增殖和存活来促进上皮细胞的转化。尽管许多研究报道了JNK在促进Fas受体介导的凋亡中起作用，但文献中很少有研究JNK在Fas受体介导的凋亡过程中的抗凋亡功能。因此，我们使用最近描述的特异性JNK抑制剂SP600125和RNA干扰来抑制前列腺癌细胞系DU 145中的内源性JNK活性。我们证明内源性JNK活性增加了一种激酶HIPK3的表达，该激酶先前已被认为与多种肿瘤的多药耐药性有关。也有报道称HIPK3可使FADD磷酸化。FADD与caspase-8之间的相互作用受到抑制，但发现JNK活性的消除或HIPK3表达的缺失可恢复这种相互作用，并增加DU 145细胞对Fas受体介导的凋亡的敏感性。总之，我们提供了新的证据表明JNK调节前列腺癌细胞中HIPK3的表达，并且这通过减少FADD与caspase-8之间的相互作用导致对Fas受体介导的凋亡的抗性增加。
