Tissues from Young Mice and Patients Are Primed for Apoptosis

The use of chemotherapy and radiation is limited by the induction of apoptosis in healthy tissues, which is especially pronounced in very young pediatric cancer patients who experience higher levels of certain treatment-related toxicities than adults. However, it is unclear why children experience a greater risk of developing these toxicities, and although apoptosis has been extensively studied in cancer and hematopoietic tissues, less is known about apoptosis in healthy somatic tissues. Sarosiek and colleagues performed BH3 profiling to determine the propensity of various cell types to undergo apoptosis. BH3-only proteins trigger mitochondrial apoptosis by activating proapoptotic proteins (BAX or BAK). Thus, by titrating BH3 peptides, mitochondria and cells can be classified as “primed” for apoptosis if the mitochondria permeabilize readily, “unprimed” if antiapoptotic proteins render them less sensitive to apoptosis, and “apoptosis refractory” if insufficient expression of apoptotic machinery prevents apoptosis. BH3 profiling of adult mouse tissues found that hematopoietic cells were primed, cells from the intestines, lungs, and liver were unprimed, and cells from the brain, heart, and kidney were refractory. The refractory tissues were lacking both pro- and antiapoptotic proteins including BAX and BAK. In contrast, brain, heart, and kidney cells in embryonic and young mice were primed for apoptosis, and radiation and chemotherapy induced extensive apoptosis. Growth-associated MYC signaling promoted high expression levels of BAK and BAX in young mice, likely explaining their susceptibility to apoptosis, whereas BAK and BAX were downregulated in adulthood. The higher apoptotic priming in young mice contributed to cardiotoxicity in response to chemotherapy and neurotoxicity in response to radiation, which could be prevented by loss of BAX and BAK. Consistent with these findings, brain tissue from young patients was most sensitive to BH3 peptides, and BAX expression was highest prenatally and decreased throughout development. The finding that tissue from young patients and mice is primed for apoptosis may explain the increased risk of certain treatment-associated toxicities in pediatric cancer patients.

Sarosiek KA, Fraser C, Muthalagu N, Bhola PD, Chang W, McBrayer SK, et al. Developmental regulation of mitochondrial apoptosis by c-Myc governs age- and tissue-specific sensitivity to cancer therapeutics. Cancer Cell 2017;31:142–56.

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