Caspase-3 activates a signaling cascade that stimulates tumor cells proliferation to resist therapy
Caspases are a specific class of cysteine proteases that play essential roles in apoptosis, necrosis, and inflammation. In the apoptotic process induced by extracellular signals, they are prominent not only in the initiation (caspase-8 and -9) but also the execution (caspase-3, -6 and -7). However, they are not essential in the apoptosis activated by intracellular stress conditions. Any dysregulation of apoptosis can cause diseases. On one hand, failure of apoptosis contributes to cancer, on the other hand, occurrence of unwanted apoptosis accompanied with Alzheimer's disease. Besides being implicated as "executioners", caspases also participate in the physiological programs of cell differentiation and act some pro-survival functions.
Recently, Li Chuan-Yuan et al. reported that under radiation therapy, caspase-3 activated a signaling cascade and stimulated tumor cells proliferation to resist therapy. It's really an interesting finding. But how does it happen?
To investigate whether dying cells in the tumor mass support the proliferation of other live tumor cells, Huang et al. used a model that mixed luciferase-labeled and unlabeled cancer cells together, monitored their growth in vitro and in vivo when they were treated lethal doses of X-rays. They found that tumor and stromal cells under radiotherapy emit a mitogenic signal and caspase-3 was required in this process. In the response of chemo- and radiotherapy, cytosolic Ca2+-independent phospholipase A2 (iPLA2) is stimulated by caspase-3-mediated proteolysis, and then generates arachidonic acid (AA). Sequentially, AA is processed and produces prostaglandin E2 (PGE2).
How does PGE2 or some other iPLA2-related products stimulate the growth of tumor cells is still unknown. It's previously demonstrated that after binding the receptor on the surface of tumor cells, PGE2 can activate the Wnt signaling pathway, which is involved in the regulation of cell proliferation. It is a hypothesis need to be clarified.
As caspase-3 activation plays a negative role in human malignancies, caspase inhibitor and/or some inhibitors that blocking PGE2 biosynthesize may contribute to prevent the recurrence of therapy resistant.
References:
Nat Med. 2011 Jul 3; 17(7): 860-6.
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Recently, Li Chuan-Yuan et al. reported that under radiation therapy, caspase-3 activated a signaling cascade and stimulated tumor cells proliferation to resist therapy. It's really an interesting finding. But how does it happen?
To investigate whether dying cells in the tumor mass support the proliferation of other live tumor cells, Huang et al. used a model that mixed luciferase-labeled and unlabeled cancer cells together, monitored their growth in vitro and in vivo when they were treated lethal doses of X-rays. They found that tumor and stromal cells under radiotherapy emit a mitogenic signal and caspase-3 was required in this process. In the response of chemo- and radiotherapy, cytosolic Ca2+-independent phospholipase A2 (iPLA2) is stimulated by caspase-3-mediated proteolysis, and then generates arachidonic acid (AA). Sequentially, AA is processed and produces prostaglandin E2 (PGE2).
How does PGE2 or some other iPLA2-related products stimulate the growth of tumor cells is still unknown. It's previously demonstrated that after binding the receptor on the surface of tumor cells, PGE2 can activate the Wnt signaling pathway, which is involved in the regulation of cell proliferation. It is a hypothesis need to be clarified.
As caspase-3 activation plays a negative role in human malignancies, caspase inhibitor and/or some inhibitors that blocking PGE2 biosynthesize may contribute to prevent the recurrence of therapy resistant.
References:
Nat Med. 2011 Jul 3; 17(7): 860-6.
Related to Caspase-3 activates a signaling cascade that stimulates tumor cells proliferation to resist therapy
   The suicidal role of caspase in Alzheimer's Disease (AD)
   While we have seen the interesting finding that caspases mediate chronic neuronal degeneration or even normal neuron function like Long Term Depression (BI6727). It is ...
   PD153035 upregulates unfolded protein response in Keratinocytes
   Epidermal keratinocytes is special tissue that keep differentiation to maintain the metabolism of the skin. The mechanism of the continuous differentiation is still not very ...
   Caspase-3 and Alzheimer's disease
   Figure 1 Caspase-3 is a key enzyme in mediating cell apoptosis. It is activated in apoptotic cells by both intrinsic (av-951) pathway and extrinsic ...
Be Sociable, Share!