Glutathione participates in the modulation of starvation-induced autophagy in carcinoma cells

Desideri, Enrico; Filomeni, Giuseppe; Ciriolo, Maria Rosa

doi:10.4161/auto.22037

Cited by 107 publications

(92 citation statements)

References 31 publications

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“…The identification of ABCG2 as a regulator of autophagy flux suggests that this transporter may confer a "transient resistance" to tumor cells under stress conditions. Recently, both ABCC1 and ABCB1 have also been suggested to play a role in autophagy, 47,48 suggesting that there may be a general role of ABC transprorters in cell survival that has not been recognized and exploited. This may be particularly important for ABCG2, since this transporter, along with ABCB1, is highly expressed in most cancer stem cells (CSCs), where it has been used for both CSC isolation and as a CSC biomarker.…”

Section: Discussionmentioning

confidence: 99%

A role for ABCG2 beyond drug transport: Regulation of autophagy

et al. 2016

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The ABC drug transporters, including ABCG2, are well known for their ability to efflux a wide spectrum of chemotherapeutic agents, thereby conferring a multidrug-resistant phenotype. However, studies over the past several years suggest that the ABC transporters may play additional role(s) in cell survival in the face of stress inducers that are not ABCG2 substrates (i.e., nutrient deprivation, ionizing radiation, rapamycin). The mechanism by which this occurs is largely unknown. In the present study, using several cancer cell lines and their ABCG2-overexpressing sublines, we show that cells overexpressing ABCG2 were more resistant to these stressors. This resistance was associated with an elevated level of autophagy flux, as measured by a higher rate of SQSTM1/p62 degradation and greater accumulation of LC3-II when compared to parental cells. Knockdown of ABCG2 reduced autophagic activity in resistant cells to a level similar to that observed in parental cells, confirming that the enhanced autophagy was ABCG2-dependent. Moreover, using cell viability, apoptosis, and clonogenic assays, we demonstrated that the ABCG2-expressing cells were more resistant to amino acid starvation and radiation-induced cell death. Importantly, knockdown of the critical autophagy factors ATG5 and ATG7 greatly reduced cell survival, verifying that enhanced autophagy was critical for this effect. Taken together, these data indicate that autophagy induced by various stressors is enhanced/accelerated in the presence of ABCG2, resulting in delayed cell death and enhanced cell survival. This defines a new role for this transporter, one with potential clinical significance.

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Section: Discussionmentioning

confidence: 99%

A role for ABCG2 beyond drug transport: Regulation of autophagy

et al. 2016

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“…48 In particular, NADPH participates in the maintenance of glutathione homeostasis, 49 a crucial determinant of the cellular redox balance, whose alteration modulates a plethora of cellular mechanisms, including autophagy, as we have demonstrated in previous works. 27,50 From this point of view, the modulation of autophagy could be at the basis of the protective effect of MAPK14 on starvation-induced cell death. In fact, although autophagy is a well-known protective mechanism that contributes to maintain cell viability by providing substrates for ATP production and macromolecules synthesis through the self-digestion of cellular components, an uncontrolled activation of autophagy may, on the contrary, be detrimental and could finally give rise to cell death.…”

Section: Discussionmentioning

confidence: 99%

MAPK14/p38α-dependent modulation of glucose metabolism affects ROS levels and autophagy during starvation

et al. 2014

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“…Inactivation of mTOR kinase activity by rapamycin (Klionsky et al 2012) or by starvation (Desideri et al 2012 reduces the level of a downstream target of mTOR, phosphorylated ribosomal protein S6 (P-S6), indicative of mTOR inhibition, which can induce autophagy in multiple cell types (Klionsky et al 2012). We sought to determine if autophagy occurs in syncytiotrophoblasts, and we used both starvation ( Fig.…”

Section: Starvation Rapamycin and Punicalagin Induce Autophagy In Cumentioning

confidence: 99%

Punicalagin promotes autophagy to protect primary human syncytiotrophoblasts from apoptosis

Wang¹,

Chen²,

Longtine³

et al. 2016

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Punicalagin is a prominent polyphenol in pomegranate juice that protects cultured syncytiotrophoblasts from stress-induced apoptosis. Here, we test the hypothesis that punicalagin has this effect by inhibiting the mTOR kinase pathway to enhance autophagic turnover and limit apoptosis in cultured primary human syncytiotrophoblasts. In syncytiotrophoblasts, starvation, rapamycin, or punicalagin all decreased the expression of phosphorylated ribosomal protein S6, a downstream target of the mTOR kinase, and of the autophagy markers, LC3-II and p62. In contrast, in the presence of bafilomycin, an inhibitor of late stages of autophagy and degradation in the autophagolysosome, syncytiotrophoblasts exposed to starvation, rapamycin, or punicalagin all showed increased levels of LC3-II and p62. The number of LC3-II punctae also increased in punicalagin-treated syncytiotrophoblasts exposed to chloroquine, another inhibitor of autophagic degradation, and punicalagin increased the number of lysosomes. The apoptosis-reducing effect of punicalagin was attenuated by inhibition of autophagy using bafilomycin or knockdown of the autophagy related gene, ATG16L1. Collectively, these data support the hypothesis that punicalagin modulates the crosstalk between autophagy and apoptosis to promote survival in cultured syncytiotrophoblasts.

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Glutathione participates in the modulation of starvation-induced autophagy in carcinoma cells

Cited by 107 publications

References 31 publications

A role for ABCG2 beyond drug transport: Regulation of autophagy

A role for ABCG2 beyond drug transport: Regulation of autophagy

MAPK14/p38α-dependent modulation of glucose metabolism affects ROS levels and autophagy during starvation

Punicalagin promotes autophagy to protect primary human syncytiotrophoblasts from apoptosis

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