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A role for ABCG2 beyond drug transport: Regulation of autophagy
Rui Ding1, Shengkan Jin1, Kirk Pabon1
1a Cancer Institute of New Jersey and Robert Wood Johnson Medical School, Rutgers, State University of New Jersey , New Brunswick , NJ , USA.
Abstract:
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.
Insights
The ABCG2 transporter enhances cancer cell survival by increasing autophagy flux, which helps cells resist stressors like nutrient deprivation and radiation. This discovery reveals a new role for ABCG2 with potential clinical applications.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- ATP-binding cassette (ABC) transporters, like ABCG2, are known for multidrug resistance.
- Emerging evidence suggests ABC transporters play roles in cell survival beyond substrate efflux, particularly under stress.
- The precise mechanisms underlying this stress-survival role remain largely unelucidated.
Purpose of the Study:
- To investigate the role of ABCG2 in cancer cell survival under various stress conditions.
- To elucidate the underlying molecular mechanisms, focusing on autophagy.
- To determine the clinical significance of ABCG2-mediated stress resistance.
Main Methods:
- Utilized cancer cell lines and ABCG2-overexpressing sublines.
- Assessed autophagy flux via SQSTM1/p62 degradation and LC3-II accumulation.
- Employed cell viability, apoptosis, and clonogenic assays.
- Performed ABCG2 and autophagy gene knockdown experiments (ATG5, ATG7).
Main Results:
- ABCG2 overexpression conferred resistance to stressors like nutrient deprivation and ionizing radiation.
- Resistant cells exhibited elevated autophagy flux, indicated by increased LC3-II and decreased SQSTM1/p62.
- ABCG2 knockdown reversed the enhanced autophagy and resistance.
- Knockdown of ATG5 or ATG7 abolished the survival advantage conferred by ABCG2.
- ABCG2-expressing cells showed increased resistance to amino acid starvation and radiation-induced death.
Conclusions:
- ABCG2 enhances autophagy flux, accelerating the autophagic response to various cellular stressors.
- This ABCG2-dependent autophagy contributes significantly to cancer cell survival under stress.
- Identified a novel, clinically relevant role for ABCG2 in promoting cell survival through autophagy modulation.
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