Apoptosis Bystander Effect

Bystander effect in apoptosis

To reciprocate the scenario of cell growth, the bystander effect can lead cells towards apoptosis. There has been conflicting reports indicating both the expression of connexins induced apoptosis and may also supress/ prolong apoptosis.

Studies have shown the expression of Cx32 in Caki-1 cells (human metastatic renal carcinoma cell line) had a suppressive effect on Caki-1 cell growth in mice and also significantly reduce the anchorage and invasiveness of the carcinoma (figure 3 (9)). By utilizing short interfering RNA (siRNA), it was confirmed that this effect was due to Src signaling inactivation, which led to the suppression of Stat3 (signal transducers and activators of transcription 3), and the reduction
There seems to be a dual function of GJPs depending on the stages of apoptosis. During the early stages of cell death, the expression of GJPs allows the transfer of the death signal from dying cells to neighboring cells. At the same time since GJPs allow bidirectional transfers, neighboring cells will attempt to restore and help the dying neighbors by supplying cellular necessities for survival (i.e. glucose, ATP, and ascorbic acid) (Bry et al., 2004; Furlan, Lecanda, Screen, & Civitelli, 2001) (figure 2 (19)). GJPs may also allow the dispersion of the death signal in order to prolong the final phases of cell death to occur. Harmful metabolites like nitric oxides can also be dispersed and limited in hope to rescue the dying cells (T Nakase, Sohl, Theis, Willecke, & Naus, 2004). Depending on the severity of shift in homeostasis, different cell fates can occur (cell survival or cell
Upon activation of Cx43 hemichannels, Src kinases and ERK/MAP kinases will be activated and promotes cell survival rather than cell death (figure 3 (19,21)). Hence, activation of Cx43 hemichannels prevented osteoporosis from occurring (L. I. Plotkin, Aguirre, Kousteni, Manolagas, & Bellido, 2005). Similarly, Cx43 hemichannels are capable of transferring survival signals from the extracellular milieu to promote cellular survival. A model has been proposed where bisphosphonates promote the opening of the nonjunctional Cx43 hemichannels by changing its conformation. Upon conformational change, there are series of steps for Src activation (figure 2 (14)). Increased Src kinase activity leads to MEK and ERK activation. The activation of Src and ERK/MAPK not only promotes cell survival (reducing the impact of death signals) (figure 2 (15,16)), but also promotes the closure of the hemichannel (Lilian I Plotkin, Manolagas, & Bellido, 2002). Depending on the molecules on the extracellular side, these hemichannels may act differently and thus elicit different cell fates. Although fluctuations of Ca2+, reduction in extracellular Ca2+, extracellular ATP and bisphosphonates promotes the opening of the hemichannel, ATP, and other metabolic inhibitors induces permanent opening configuration, which leads to cell death (Beyer & Steinberg, 1991;