Geletu Mulu, Taha Zaid, Gunning Patrick T, Raptis Leda
Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada.
Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada.
Cancers (Basel). 2019 Feb 1;11(2):167. doi: 10.3390/cancers11020167.
Gap junctional, intercellular communication (GJIC) is interrupted in cells transformed by oncogenes such as activated Src. The Src effector, Ras, is required for this effect, so that Ras inhibition restores GJIC in Src-transformed cells. Interestingly, the inhibition of the Src effector phosphatidyl-inositol-3 kinase (PI3k) or Signal Transducer and Activator of Transcription-3 (Stat3) pathways does not restore GJIC. In the contrary, inhibition of PI3k or Stat3 in non-transformed rodent fibroblasts or epithelial cells or certain human lung carcinoma lines with extensive GJIC inhibits communication, while mutational activation of PI3k or Stat3 increases GJIC. Therefore, it appears that oncogenes such as activated Src have a dual role upon GJIC; acting as inhibitors of communication through the Ras pathway, and as activators through activation of PI3k or Stat3. In the presence of high Src activity the inhibitory functions prevail so that the net effect is gap junction closure. PI3k and Stat3 constitute potent survival signals, so that their inhibition in non-transformed cells triggers apoptosis which, in turn, has been independently demonstrated to suppress GJIC. The interruption of gap junctional communication would confine the apoptotic event to single cells and this might be essential for the maintenance of tissue integrity. We hypothesize that the GJIC activation by PI3k or Stat3 may be linked to their survival function.
间隙连接介导的细胞间通讯（GJIC）在被癌基因（如活化的Src）转化的细胞中会被中断。Src效应分子Ras参与了这一过程，因此抑制Ras可恢复Src转化细胞中的GJIC。有趣的是，抑制Src效应分子磷脂酰肌醇-3激酶（PI3k）或信号转导及转录激活因子-3（Stat3）途径并不能恢复GJIC。相反，在具有广泛GJIC的未转化啮齿动物成纤维细胞、上皮细胞或某些人肺癌细胞系中抑制PI3k或Stat3会抑制通讯，而PI3k或Stat3的突变激活则会增加GJIC。因此，活化的Src等癌基因似乎对GJIC具有双重作用；通过Ras途径作为通讯抑制剂，通过激活PI3k或Stat3作为激活剂。在Src高活性存在的情况下，抑制功能占主导，因此净效应是间隙连接关闭。PI3k和Stat3构成强大的生存信号，因此在未转化细胞中抑制它们会引发凋亡，而凋亡又已被独立证明可抑制GJIC。间隙连接通讯的中断会将凋亡事件限制在单个细胞内，这可能对维持组织完整性至关重要。我们推测PI3k或Stat3对GJIC的激活可能与其生存功能有关。
