Apoptosis: Breaking Up Is Hard To Do

Apoptosis: Breaking Up Is Hard To Do

Apoptosis is the most well-understood mechanism of programmed cell death (PCD). The term apoptosis was coined in 1972 by Kerr et al.4 to describe a form of cell death characterized by nuclear and cytoplasmic  condensation followed by the breaking up of the cell into a number of membrane-bound fragments4,6. Apoptosis has traditionally been identified experimentally as a constellation of three features: translocation of phosphatidyl serine to the outer layer of the cell membrane, detected by the acquisition of Annexin V binding, loss of membrane integrity, detected by the inability to exclude vital dyes, and the generation of a characteristic DNA ladder of nucleosome-sized segments6.

Apoptosis is a highly regulated process initiated by specific biochemical signals. There are two main pathways leading to apoptosis: intrinsic and extrinsic2,3,5,7. The intrinsic pathway is triggered by conditions such as DNA damage, ER stress, or hypoxia2,3,7.  It is characterized by mitochondrial outer membrane permeabilization (MOMP), which is regulated by members of the Bcl-2 protein family. BH3 subfamily proteins (BIM, BAD, PUMA, NOXA)7 activate BAX and BAK which cause permeabilization of the mitochondrial outer membrane (MOMP)2,3,7. MOMP results in leakage of cytochrome c, SMAC, and HTRA2 into the cytoplasm. Cytochrome c combines with APAF1 to form a complex called the apoptosome2,3,5. Apoptosome assembly results in the activation of caspase 9 and other initiator caspases, which results in the activation of the executioner caspases, caspases 3 and 7. Progression of apoptosis is negatively regulated by members of the Bcl-2 family including Bcl-2, Bcl-XL, and MCL-13,7, and by the caspase inhibitor XIAP2. When apoptosis is initiated, BH3 proteins block the activity of Bcl-2, and XIAP activity is blocked by SMAC, HTRA2, and ARTS, allowing apoptosis to proceed2.

The extrinsic pathway is triggered by signaling through death receptors such as CD95/FAS and TRAILR2,3,5.  Triggering of these receptors transmits a signal through a receptor-associated protein complex called the death-inducing signaling complex (DISC)5,8. Stimulation of the DISC results in autocatalytic activation of caspases 8 and 10, the initiator caspases for the extrinsic pathway3,5,8. When significant amounts of cFLIP are present in the DISC, activation of caspases 8 and 10 is blocked and apoptosis is inhibited5,8. Activation of Caspases 8 and 10 ultimately leads to activation of caspases 3 and 7, the executioner caspases, where the two pathways merge3,5,8. Activation of caspases 3 and 7 further leads to the final catastrophic events in cell death, including DNA fragmentation, cytoplasmic condensation, and membrane blebbing2,3,5,9.

Recently, regulation of apoptosis has become an exciting target for cancer therapy. Many tumor cells exhibit resistance to apoptosis due to over-expression of Bcl-2-related survival proteins and/or decreased BH3 protein expression1. New drugs known as BH3 mimetics are being developed to inhibit the activity of Bcl-2 survival proteins and enhance BH3-like pro-apoptotic activity in these cells1.

References

  1. Adams JM, Cory S. 2018. The BCL-2 arbiters of apoptosis and their growing role as cancer targets. Cell Death Differ. 25(1):27-36. PMID: 29099483.
  2. Fuchs Y, Steller H. 2015. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat Rev Mol Cell Biol. 16(6):329-44. PMID: 25991373.
  3. Ichim G, Tait SW. 2016. A fate worse than death: apoptosis as an oncogenic process. Nat Rev Cancer. 16(8):539-48. PMID: 27364482.
  4. Kerr JF, Wyllie AH, Currie AR. 1972. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26(4):239-57. PMID: 4561027.
  5. Krammer PH, Arnold R, Lavrik IN. 2007. Life and death in peripheral T cells. Nat Rev Immunol. 7(7):532-42. PMID: 17589543.
  6. Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nuñez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G; Nomenclature Committee on Cell Death 2009. 2009. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 16(1):3-11. PMID: 18846107.
  7. Pihán P, Carreras-Sureda A, Hetz C. 2017. BCL-2 family: integrating stress responses at the ER to control cell demise. Cell Death Differ. 24(9):1478-1487. PMID: 28622296.
  8. Tsuchiya Y, Nakabayashi O, Nakano H. 2015. FLIP the Switch: Regulation of Apoptosis and Necroptosis by cFLIP.  Int J Mol Sci. 16(12):30321-41. PMID: 26694384.
  9. Zhang Y, Chen X, Gueydan C, Han J. 2018. Plasma membrane changes during programmed cell deaths. Cell Res. 28(1):9-21. PMID: 29076500.

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