Dual Role of 3-Methyladenine in Modulation of Autophagy via Different Temporal Patterns of Inhibition on Class I and III Phosphoinositide 3-Kinase*
By Youtong Wu, Hui-Ling Tan, G. Shui, C. Bauvy, Qing Huang, Markus R. Wenk, C. Ong, P. Codogno, Han-Ming Shen. Journal of Biological Chemistry, 2010
1,065 citations recorded by the source corpus.
A group of phosphoinositide 3-kinase (PI3K) inhibitors, such as 3-methyladenine (3-MA) and wortmannin, have been widely used as autophagy inhibitors based on their inhibitory effect on class III PI3K activity, which is known to be essential for induction of autophagy. In this study, we systematically examined and compared the effects of these two inhibitors on autophagy under both nutrient-rich and deprivation conditions. To our surprise, 3-MA is found to promote autophagy flux when treated under nutrient-rich conditions with a prolonged period of treatment, whereas it is still capable of suppressing starvation-induced autophagy. We first observed that there are marked increases of the autophagic markers in cells treated with 3-MA in full medium for a prolonged period of time (up to 9 h). Second, we provide convincing evidence that the increase of autophagic markers is the result of enhanced autophagic flux, not due to suppression of maturation of autophagosomes or lysosomal function. More importantly, we found that the autophagy promotion activity of 3-MA is due to its differential temporal effects on class I and class III PI3K; 3-MA blocks class I PI3K persistently, whereas its suppressive effect on class III PI3K is transient. Because 3-MA has been widely used as an autophagy inhibitor in the literature, understanding the dual role of 3-MA in autophagy thus suggests that caution should be exercised in the application of 3-MA in autophagy study.
Subfields: Epidemiology
View Paper: https://www.semanticscholar.org/paper/4529e9c9ec39f71df18c5adde206360922a5c631
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Citations in the corpus
- Guidelines for the use and interpretation of assays for monitoring autophagy (2012, methodology): “Thus, wortmannin may be considered as an alternative to 3-MA for autophagy inhibition.(257) However, wortmannin can induce the formation of vacuoles that may have the appearance of autophagosomes, although they are swollen late endocytic compartments.”
- Autophagy and apoptosis dysfunction in neurodegenerative disorders. (2014, positive): “Although the interpretation of protection via autophagy inhibition should be qualified because this inhibitor has a dual role in modulation of autophagy via different temporal patterns of inhibition on class I and class III phosophoinositide 3-kinase (Wu et al., 2010).”
- Molecular characterization of LC3-associated phagocytosis (LAP) reveals distinct roles for Rubicon, NOX2, and autophagy proteins (2015, positive): “A RT I C L E S with 3-MA treatment, which inhibits VPS34 activity 5,8,35 (Fig.”
- Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, positive): “Sequestration inhibitors, including 3-MA, LY294002 and wortmannin, inhibit class I phosphoinositide 3-kinases (PI3Ks) as well as class III PtdIns3Ks.(132,330,1145) The class I enzymes generate products such as PtdIns(3,4,5)P3 that inhibit autophagic sequestration, whereas the class III product (PtdI”