Molecular mechanism of apoptosis induced by mechanical forces

In all biological systems, a balance between cell proliferation/growth and death is required for normal development as well as for adaptation to a changing environment. To affect their fate, it is essential for cells to integrate signals from the environment. Recently, it has been recognized that physical forces such as stretch, strain, and tension play a critical role in regulating this process. Despite intensive investigation, the pathways by which mechanical signals are converted to biochemical responses is yet to be completely understood. In this review, we will examine our current understanding of how mechanical forces induce apoptosis in a variety of biological systems. Rather than being a degenerative event, physical forces act through specific receptor-like molecules such as integrins, focal adhesion proteins, and the cytoskeleton. These molecules in turn activate a limited number of protein kinase pathways (p38 MAPK and JNK/SAPK), which amplify the signal and activate enzymes (caspases) that promote apoptosis. Physical forces concurrently activate other signaling pathways such as PIK-3 and Erk 1/2 MAPK, which modulate the apoptotic response. The cell phenotype and the character of the physical stimuli determine which pathways are activated and, consequently, allow for variability in response to a specific stimulus in different cell types.