Soh J W, Mao Y, Kim M G, Pamukcu R, Li H, Piazza G A, Thompson W J, Weinstein I B
Department of Medicine and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Clin Cancer Res. 2000 Oct;6(10):4136-41.
Sulindac sulfone (Exisulind) induces apoptosis and exhibits cancer chemopreventive activity, but in contrast to sulindac, it does not inhibit cyclooxygenases 1 or 2. We found that sulindac sulfone and two potent derivatives, CP248 and CP461, inhibited the cyclic GMP (cGMP) phosphodiesterases (PDE) 2 and 5 in human colon cells, and these compounds caused rapid and sustained activation of the c-Jun NH2-terminal kinase 1 (JNK1). Rapid activation of stress-activated protein/ERK kinase 1 (SEK1) and mitogen-activated protein kinase kinase kinase (MEKK1), which are upstream of JNK1, was also observed. Other compounds that increase cellular levels of cGMP also activated JNK1, and an inhibitor of protein kinase G (PKG), Rp-8-pCPT-cGMPS, inhibited JNK1 activation by the sulindac sulfone derivatives. Expression of a dominant-negative JNK1 protein inhibited CP248-induced cleavage of poly(ADP-ribose) polymerase, a marker of apoptosis. Thus, it appears that sulindac sulfone and related compounds induce apoptosis, at least in part, through activation of PKG, which then activates the MEKK1-SEK1-JNK1 cascade. These studies also indicate a role for cGMP and PKG in the JNK pathway.
舒林酸砜（依西美坦）可诱导细胞凋亡并具有癌症化学预防活性，但与舒林酸不同的是，它并不抑制环氧化酶1或2。我们发现舒林酸砜以及两种强效衍生物CP248和CP461可抑制人结肠细胞中的环磷酸鸟苷（cGMP）磷酸二酯酶（PDE）2和5，并且这些化合物可引起c-Jun氨基末端激酶1（JNK1）的快速持续激活。还观察到JNK1上游的应激激活蛋白/ERK激酶1（SEK1）和丝裂原活化蛋白激酶激酶激酶（MEKK1）的快速激活。其他可增加细胞内cGMP水平的化合物也可激活JNK1，并且蛋白激酶G（PKG）的抑制剂Rp-8-pCPT-cGMPS可抑制舒林酸砜衍生物对JNK1的激活。显性负性JNK1蛋白的表达可抑制CP248诱导的聚（ADP-核糖）聚合酶的裂解，聚（ADP-核糖）聚合酶是细胞凋亡的标志物。因此，似乎舒林酸砜及相关化合物至少部分通过激活PKG来诱导细胞凋亡，PKG随后激活MEKK1-SEK1-JNK1级联反应。这些研究还表明cGMP和PKG在JNK途径中发挥作用。
