Chapter 5 │ Page 171 Cx40, and Cx43 protein- associated GJs increased in HeLa cells, only Cx26 proteins inhibited tumor growth and proliferation [88]. The authors observed that all three transfected Cxs communicated to a similar extent via GJ coupling, so the di erence in their tumorigenicity may be related, at least in part, to the pattern of Cxs localization in the cells [88]. Altogether, these results demonstrated that GJs also have anti-tumorigenic properties, GJs-independent mechanisms of tumor suppression must be considered in order to find adequate therapeutic targets. Tumor-suppressing properties are also described to be specific to Cx subtypes. Sirnes et al. demonstrated a mechanism by which Cx43 proteins specifically were able to reduce tumor growth and induce apoptosis in colon cancer cells. Cx43 proteins were found to be partly colocalized with ꞵ-catenin at the plasma membrane and inhibited Wnt signaling [94]. Wnt signaling has a key role in disease development and deregulation of the pathway is connected to cancer and metastasis [95]. ꞵ-catenin is one of the proteins which regulate Wnt signaling [95], and thus inhibition of Wnt signaling by ꞵ-catenin targeting via Cx43 upregulation may suppress tumor development. Another mechanism by which Cxs and GJs may act as tumor suppressor has been proposed for the Cx37 subtype. Burt and co-workers reported that Cx37 protein expression suppressed cell proliferation in tumorigenic rat insulinoma cells by significantly extending the duration of some phases of the cell cycle (gap 1 (G1), synthesis (S), and gap 2 (G2)) and accumulating cells at the G1/S checkpoint [89]. Since cancer cells a ect the normal interphase processes [96], extension of several cell cycle phases may slow down the progression of malignant cells. In addition, cell proliferation was also suppressed via the CT domain and pore-forming domains of Cx37 proteins, independently of connexon or GJ formation [97]. Therefore, Cx37 proteins can suppress tumor proliferation and growth by di erent mechanisms, such as a ecting the interphase processes of the cell cycle and modulation of both the CT domain and pore-forming domains of Cx37 proteins. Lastly, the Cx32 protein also demonstrated tumoricidal e ects in
RkJQdWJsaXNoZXIy MTk4NDMw