The role of GABARAPL1/GEC1 in autophagic flux and mitochondrial quality control in MDA-MB-436 breast cancer cells

Boyer-Guittaut, Michaël; Poillet-Perez, Laura; Liang, Qiwei; Bôle‐Richard, Elodie; Ouyang, Xiaosen; Benavides, Gloria A.; Chakrama, Fatima-Zahra; Fraîchard, Annick; Darley‐Usmar, Victor; Despouy, Gilles; Jouvenot, Michèle; Delage-Mourroux, Régis; Zhang, Jianhua

doi:10.4161/auto.28390

Cited by 84 publications

(73 citation statements)

References 63 publications

(79 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Autophagy is involved in recycling of damaged cellular organelles, including mitochondria. It is the primary mechanism for removing damaged mitochondria and plays an important role in maintaining mitochondrial homeostasis in cells [56–58]. Reports show that inhibition of autophagy results in accumulation of damaged mitochondria [31–33].…”

Section: Discussionmentioning

confidence: 99%

Autophagy inhibition re-sensitizes pulse stimulation-selected paclitaxel-resistant triple negative breast cancer cells to chemotherapy-induced apoptosis

Wen

Yeo

Wang

et al. 2015

Breast Cancer Res Treat

View full text Add to dashboard Cite

Chemotherapy is the mainstay of systemic treatment for triple negative breast cancer (TNBC); however, the development of drug resistance limits its effectiveness. Therefore, we investigated the underlying mechanism for drug resistance and potential approaches to overcome it for a more effective treatment for TNBCs. Using a pulse-stimulated selection strategy to mimic chemotherapy administration in the clinic, we developed a new paclitaxel-resistant MDA-MB-231 cell line and analyzed these cells for changes in autophagy activity, and the role and mechanisms of the increased autophagy in promoting drug resistance were determined. We found that the pulse-stimulated selection strategy with paclitaxel resulted in MDA-MB-231 variant cells with enhanced resistance to paclitaxel. These resistant cells were found to have enhanced basal autophagy activity, which confers a cytoprotective function under paclitaxel treatment stress. Inhibition of autophagy enhanced paclitaxel-induced cell death in these paclitaxel-resistant cells. We further revealed that up-regulated autophagy in resistant cells enhanced the clearance of damaged mitochondria. Last, we showed that the paclitaxel-resistant cancer cells acquired cross resistance to epirubicin and cisplatin. Together, these results suggest that combining autophagy inhibition with chemotherapy may be an effective strategy to improve treatment outcome in paclitaxel-resistant TNBC patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Autophagy inhibition re-sensitizes pulse stimulation-selected paclitaxel-resistant triple negative breast cancer cells to chemotherapy-induced apoptosis

Wen

Yeo

Wang

et al. 2015

Breast Cancer Res Treat

View full text Add to dashboard Cite

show abstract

“…Quantitative real-time PCR was performed using SYBR green in an ABI 7500 machine. Mitochondrial DNA copy number was determined by normalizing results from primers targeted to mtDNA (Forward: 5'-CCAAGGAATTCCCCTACACA-3' and Reverse: 5′-GAAATTGCGAGAATGGTGGT-3′) against results from primers targeted to nuclear 18S DNA (Forward: 5'-CGAAAGCATTTGCCAAGAAT-3' and Reverse: [38], [39]. Mitochondrial DNA damage was determined by PCR as previously described [40].…”

Section: Methodsmentioning

confidence: 99%

Inhibition of autophagy with bafilomycin and chloroquine decreases mitochondrial quality and bioenergetic function in primary neurons

et al. 2017

Self Cite

View full text Add to dashboard Cite

Autophagy is an important cell recycling program responsible for the clearance of damaged or long-lived proteins and organelles. Pharmacological modulators of this pathway have been extensively utilized in a wide range of basic research and pre-clinical studies. Bafilomycin A1 and chloroquine are commonly used compounds that inhibit autophagy by targeting the lysosomes but through distinct mechanisms. Since it is now clear that mitochondrial quality control, particularly in neurons, is dependent on autophagy, it is important to determine whether these compounds modify cellular bioenergetics. To address this, we cultured primary rat cortical neurons from E18 embryos and used the Seahorse XF96 analyzer and a targeted metabolomics approach to measure the effects of bafilomycin A1 and chloroquine on bioenergetics and metabolism. We found that both bafilomycin and chloroquine could significantly increase the autophagosome marker LC3-II and inhibit key parameters of mitochondrial function, and increase mtDNA damage. Furthermore, we observed significant alterations in TCA cycle intermediates, particularly those downstream of citrate synthase and those linked to glutaminolysis. Taken together, these data demonstrate a significant impact of bafilomycin and chloroquine on cellular bioenergetics and metabolism consistent with decreased mitochondrial quality associated with inhibition of autophagy.

show abstract

“…In contrast, Novak et al . (41–43) found that GABARAPL1 colocalizes with depolarized mitochondria during basal, starvation, and apoptotic conditions. GABARAPL1 deficiency attenuates autophagic flux including mitophagy and results in accumulation of damaged mitochondria (43).…”

Section: Functions Of Lc3/gabarap Family Proteins In Autophagymentioning

confidence: 99%

LC3/GABARAP family proteins: autophagy‐(un)related functions

et al. 2016

View full text Add to dashboard Cite

From yeast to mammals, autophagy is an important mechanism for sustaining cellular homeostasis through facilitating the degradation and recycling of aged and cytotoxic components. During autophagy, cargo is captured in double-membraned vesicles, the autophagosomes, and degraded through lysosomal fusion. In yeast, autophagy initiation, cargo recognition, cargo engulfment, and vesicle closure is Atg8 dependent. In higher eukaryotes, Atg8 has evolved into the LC3/GABARAP protein family, consisting of 7 family proteins [LC3A (2 splice variants), LC3B, LC3C, GABARAP, GABARAPL1, and GABARAPL2]. LC3B, the most studied family protein, is associated with autophagosome development and maturation and is used to monitor autophagic activity. Given the high homology, the other LC3/GABARAP family proteins are often presumed to fulfill similar functions. Nevertheless, substantial evidence shows that the LC3/GABARAP family proteins are unique in function and important in autophagy-independent mechanisms. In this review, we discuss the current knowledge and functions of the LC3/GABARAP family proteins. We focus on processing of the individual family proteins and their role in autophagy initiation, cargo recognition, vesicle closure, and trafficking, a complex and tightly regulated process that requires selective presentation and recruitment of these family proteins. In addition, functions unrelated to autophagy of the LC3/GABARAP protein family members are discussed.-Schaaf, M. B. E., Keulers, T. G, Vooijs, M. A., Rouschop, K. M. A. LC3/GABARAP family proteins: autophagy-(un)related functions.

show abstract

The role of GABARAPL1/GEC1 in autophagic flux and mitochondrial quality control in MDA-MB-436 breast cancer cells

Cited by 84 publications

References 63 publications

Autophagy inhibition re-sensitizes pulse stimulation-selected paclitaxel-resistant triple negative breast cancer cells to chemotherapy-induced apoptosis

Autophagy inhibition re-sensitizes pulse stimulation-selected paclitaxel-resistant triple negative breast cancer cells to chemotherapy-induced apoptosis

Inhibition of autophagy with bafilomycin and chloroquine decreases mitochondrial quality and bioenergetic function in primary neurons

LC3/GABARAP family proteins: autophagy‐(un)related functions

Contact Info

Product

Resources

About