Mechanism and medical implications of mammalian autophagy

Đikić, Ivan; Elazar, Zvulun

doi:10.1038/s41580-018-0003-4

Cited by 2,233 publications

(1,998 citation statements)

References 201 publications

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“…Under nutrient replete conditions, mTORC1 phosphorylates ULK1 and ATG13, inhibiting autophagy initiation . On starvation, ULK1 is dephosphorylated followed by autophosphorylation and phosphorylation of ATG13 and FIP200, leading to a rapid induction of autophagy . Furthermore, autophagy can be enhanced as well by an energetic stress response mediated by the AMP‐activated protein kinase (AMPK).…”

Section: Role and Regulation Of Autophagy In Cancermentioning

confidence: 99%

Autophagy and mitochondrial metabolism: insights into their role and therapeutic potential in chronic myeloid leukaemia

2018

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Despite the development of selective BCR-ABL-targeting tyrosine kinase inhibitors (TKIs) transforming the management of chronic myeloid leukaemia (CML), therapy-resistant leukaemic stem cells (LSCs) persist after TKI treatment and present an obstacle to a CML cure. Recently, we and others have made significant contributions to the field by unravelling survival dependencies in LSCs to work towards the goal of eradicating LSCs in CML patients. In this review, we describe these findings focusing on autophagy and mitochondrial metabolism, which have recently been uncovered as two essential processes for LSCs quiescence and survival respectively. In addition, we discuss the therapeutic potential of autophagy and mitochondrial metabolism inhibition as a strategy to eliminate CML cells in patients where the resistance to TKI is driven by BCR-ABL-independent mechanism(s).

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Section: Role and Regulation Of Autophagy In Cancermentioning

confidence: 99%

Autophagy and mitochondrial metabolism: insights into their role and therapeutic potential in chronic myeloid leukaemia

2018

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“…5 LBH589 (panobinostat), a non-selective histone deacetylase inhibitor (pan-HDAC inhibitor), has been shown to induce tumour shrinkage and sustain stable disease status in a phase II trial of pre-treated lung cancer patients. 8,9 BNIP3 (Bcl-2/adenovirus E1B 19 kD protein-interacting protein 3) is a pro-cell death member of the Bcl-2 family and contains only the BH3 domain. 7 Autophagy is a self-digesting catabolic process induced under various stress conditions for homoeostatic cellular recycling that has been implicated in the progression of many diseases, including cancer and neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

Platinum‐based combination chemotherapy triggers cancer cell death through induction of BNIP3 and ROS, but not autophagy

Chung

Tang

et al. 2019

J Cellular Molecular Medi

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These days, cancer can still not be effectively cured because cancer cells readily develop resistance to anticancer drugs. Therefore, an effective combination of drugs with different mechanisms to prevent drug resistance has become a very important issue. Furthermore, the BH3-only protein BNIP3 is involved in both apoptotic and autophagic cell death. In this study, lung cancer cells were treated with a chemotherapy drug alone or in combination to identify the role of BNIP3 and autophagy in combination chemotherapy for treating cancer. Our data revealed that various combinational treatments of two drugs could increase cancer cell death and cisplatin in combination with rapamycin or LBH589, which triggered the cell cycle arrest at the S phase. Cells with autophagosome and pEGFP-LC3 puncta increased when treated with drugs. To confirm the role of autophagy, cancer cells were pre-treated with the autophagy inhibitor 3-methyladenine (3-MA). 3-MA sensitized cancer cells to chemotherapy drug treatments. These results suggest that autophagy may be responsible for cell survival in combination chemotherapy for lung cancer. Moreover, BNIP3 was induced and localized in mitochondria when cells were treated with drugs. The transfection of a dominant negative transmembrane deletion construct of BNIP3 (BNIP3ΔTM) and treatment of a reactive oxygen species (ROS) inhibitor suppressed chemo drug-induced cell death. These results indicate that BNIP3 and ROS may be involved in combination chemo drug-induced cell death. However, chemo drug-induced autophagy may protect cancer cells from drug cytotoxicity. As a result, inhibiting autophagy may improve the effects of combination chemotherapy when treating lung cancer. K E Y W O R D S autophagy, BNIP3, combination chemotherapy, reactive oxygen species How to cite this article: Chung L-Y, Tang S-J, Wu Y-C, et al. Platinum-based combination chemotherapy triggers cancer cell death through induction of Bnip3 and ROS, but not autophagy.

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“…Another physiological cellular process involved in this mechanism is autophagy, which is one route of lysosome degradation that regulates cellular lipid metabolism and controls the innate immune activation, improving the state of insulin resistance and cancer (Dikic and Elazar, 2018[7]). Several works reported the beneficial effects of autophagy in carcinogenesis and studies of GLP-1 analogs have shown its ability to increase autophagy (He et al, 2016[12]; Li et al, 2017[17]).…”

Section: Discussionmentioning

confidence: 99%