Autophagy, Bafilomycin and Cell Death: The “A-B-Cs” of Plecomacrolide-Induced Neuroprotection

“…These included 3-methyladenine (10 mM), which is a PtdIns 3-kinase inhibitor, 35 chloroquine (CQ) (25 mM), a weak base that prevents acidification and fusion between the autophagosome and the lysosome, 36 and bafilomycin A 1 (100 nM), which is an inhibitor of the vacuolar-type H + -ATPase (V-ATPase). 37 Due in large part to the toxicity of 3-methyladenine and bafilomycin A 1 (or their vehicles), chloroquine was chosen as the pharmacological inhibitor of autophagy in our experimental system. Figure 3A indicates that exposure to CQ alone produced an increase in formation of autophagosomal vesicles, consistent with the weak base's ability to prevent the completion of autophagy by interfering with acidification.…”

Section: Resultsmentioning

confidence: 99%

Dual functions of autophagy in the response of breast tumor cells to radiation

et al. 2012

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In MCF-7 breast tumor cells, ionizing radiation promoted autophagy that was cytoprotective; pharmacological or genetic interference with autophagy induced by radiation resulted in growth suppression and/or cell killing (primarily by apoptosis). The hormonally active form of vitamin D, 1,25D 3 , also promoted autophagy in irradiated MCF-7 cells, sensitized the cells to radiation and suppressed the proliferative recovery that occurs after radiation alone. 1,25D 3 enhanced radiosensitivity and promoted autophagy in MCF-7 cells that overexpress Her-2/neu as well as in p53 mutant Hs578t breast tumor cells. In contrast, 1,25D 3 failed to alter radiosensitivity or promote autophagy in the BT474 breast tumor cell line with low-level expression of the vitamin D receptor. Enhancement of MCF-7 cell sensitivity to radiation by 1,25D 3 was not attenuated by a genetic block to autophagy due largely to the promotion of apoptosis via the collateral suppression of protective autophagy. However, MCF-7 cells were protected from the combination of 1,25D 3 with radiation using a concentration of chloroquine that produced minimal sensitization to radiation alone. The current studies are consistent with the premise that while autophagy mediates a cytoprotective function in irradiated breast tumor cells, promotion of autophagy can also confer radiosensitivity by vitamin D (1,25D 3 ). As both cytoprotective and cytotoxic autophagy can apparently be expressed in the same experimental system in response to radiation, this type of model could be utilized to distinguish biochemical, molecular and/or functional differences in these dual functions of autophagy.

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“…In this case, autophagy continues until mitochondria are destroyed, thus depriving the cells of any possibility of recovery. [47][48][49] The genetic analysis of autophagy in yeast, primarily by Klionsky and others, 50,51 the extension of the genetics to mammalian cells, primarily by Levine,[52][53][54] and the development of new tools to study lysosomes, including fluorescent markers 55 and lysosome-specific drugs 56,57 have clarified the situation considerably and allowed much closer examination of what autophagy does. It now appears that autophagy usually protects cells 5,58 in that cells that can activate autophagy withstand many types of stresses far better than cells that cannot.…”

Section: Open Questionsmentioning

confidence: 99%

Programmed cell death 50 (and beyond)

Lockshin

2015

Cell Death Differ

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In the 50 years since we described cell death as 'programmed,' we have come far, thanks to the efforts of many brilliant researchers, and we now understand the mechanics, the biochemistry, and the genetics of many of the ways in which cells can die. This knowledge gives us the resources to alter the fates of many cells. However, not all cells respond similarly to the same stimulus, in either sensitivity to the stimulus or timing of the response. Cells prevented from dying through one pathway may survive, survive in a crippled state, or die following a different pathway. To fully capitalize on our knowledge of cell death, we need to understand much more about how cells are targeted to die and what aspects of the history, metabolism, or resources available to individual cells determine how each cell reaches and crosses the threshold at which it commits to death.

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Autophagy, Bafilomycin and Cell Death: The “A-B-Cs” of Plecomacrolide-Induced Neuroprotection

Cited by 106 publications

References 17 publications

LAMP2A overexpression in breast tumors promotes cancer cell survival via chaperone-mediated autophagy

LAMP2A overexpression in breast tumors promotes cancer cell survival via chaperone-mediated autophagy

Dual functions of autophagy in the response of breast tumor cells to radiation

Programmed cell death 50 (and beyond)

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