Amiodarone as an autophagy promoter reduces liver injury and enhances liver regeneration and survival in mice after partial hepatectomy

Lin, Cheng-Wei; Chen, Yaw Sen; Lin, Chia‐Yu; Chen, Yun Ju; Lo, Gin Ho; Lee, Po‐Huang; Kuo, Po Lin; Dai, Chia Yen; Huang, Jiun-Chi; Chun-g, Wang; Yu, Ming

doi:10.1038/srep15807

Cited by 55 publications

(65 citation statements)

References 32 publications

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“…Amiodarone as an autophagy inducer could reduce liver injury and promote LR after partial hepatectomy, and amiodarone-treated patients showed no evident toxicity. (27,28) Similarly, our results demonstrate that amiodarone is an antitumor agent against liver tumor formation. However, Kowalik et al reported that amiodarone-induced autophagy stimulated the proliferation of keratin 19 (a progenitor cell marker) preneoplastic lesions, leading to HCC progression at a very early stage in a rat model.…”

Section: Discussionsupporting

confidence: 73%

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Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system

Lan

et al. 2018

Hepatology

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Dysfunction of degradation machineries causes cancers, including hepatocellular carcinoma (HCC). Overexpression of cyclin D1 in HCC has been reported. We previously reported that autophagy preferentially recruits and degrades the oncogenic microRNA (miR)‐224 to prevent HCC. Therefore, in the present study, we attempted to clarify whether cyclin D1 is another oncogenic factor selectively regulated by autophagy in HCC tumorigenesis. Initially, we found an inverse correlation between low autophagic activity and high cyclin D1 expression in tumors of 147 HCC patients and three murine models, and these results taken together revealed a correlation with poor overall survival of HCC patients, indicating the importance of these two events in HCC development. We found that increased autophagic activity leads to cyclin D1 ubiquitination and selective recruitment to the autophagosome (AP) mediated by a specific receptor, sequestosome 1 (SQSTM1), followed by fusion with lysosome and degradation. Autophagy‐selective degradation of ubiquitinated cyclin D1 through SQSTM1 was confirmed using cyclin D1/ubiquitin binding site (K33‐238R) and phosphorylation site (T286A) mutants, lentivirus‐mediated silencing autophagy‐related 5 (ATG5), autophagy‐related 7 (ATG7), and Sqstm1 knockout cells. Functional studies revealed that autophagy‐selective degradation of cyclin D1 plays suppressive roles in cell proliferation, colony, and liver tumor formation. Notably, an increase of autophagic activity by pharmacological inducers (amiodarone and rapamycin) significantly suppressed tumor growth in both the orthotopic liver tumor and subcutaneous tumor xenograft models. Our findings provide evidence of the underlying mechanism involved in the regulation of cyclin D1 by selective autophagy to prevent tumor formation. Conclusion: Taken together, our data demonstrate that autophagic degradation machinery and the cell‐cycle regulator, cyclin D1, are linked to HCC tumorigenesis. We believe these findings may be of value in the development of alternative therapeutics for HCC patients. (Hepatology 2018;68:141‐154).

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Section: Discussionsupporting

confidence: 73%

“…Amiodarone as an autophagy inducer could reduce liver injury and promote LR after partial hepatectomy, and amiodarone‐treated patients showed no evident toxicity . Similarly, our results demonstrate that amiodarone is an antitumor agent against liver tumor formation.…”

Section: Discussionsupporting

confidence: 71%

Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system

Lan

et al. 2018

Hepatology

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“…As such it represents a drug of clinical interest where autophagy activation may be achieved, without further complicating effects of MTOR inhibition. For instance, induction of autophagy by amiodarone has been implicated in enhancing survival in mice following hepatectomy, 47 and supressing hepatocellular carcinoma 48 . In our study we clearly show that amiodarone is capable of activating noncanonical autophagy and endolysosomal LC3 lipidation in parallel to its effects on autophagosome formation, a parallel activity that will be important to consider.…”

Section: Discussionsupporting

confidence: 56%

Pharmacological modulators of autophagy activate a parallel noncanonical pathway driving unconventional LC3 lipidation

et al. 2017

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The modulation of canonical macroautophagy/autophagy for therapeutic benefit is an emerging strategy of medical and pharmaceutical interest. Many drugs act to inhibit autophagic flux by targeting lysosome function, while others were developed to activate the pathway. Here, we report the surprising finding that many therapeutically relevant autophagy modulators with lysosomotropic and ionophore properties, classified as inhibitors of canonical autophagy, are also capable of activating a parallel noncanonical autophagy pathway that drives MAP1LC3/LC3 lipidation on endolysosomal membranes. Further, we provide the first evidence supporting drug-induced noncanonical autophagy in vivo using the local anesthetic lidocaine and human skin biopsies. In addition, we find that several published inducers of autophagy and mitophagy are also potent activators of noncanonical autophagy. Together, our data raise important issues regarding the interpretation of LC3 lipidation data and the use of autophagy modulators, and highlight the need for a greater understanding of the functional consequences of noncanonical autophagy.

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“…However, CADs often have multiple effects within the cell and can in some cases induce or inhibit autophagy. CADs such as amiodarone, fluoxetine, imipramine and amitriptyline all have been shown to induce autophagy and have no effect on mTOR signaling (39-42). Our study demonstrates that incorporating a specific structural motif (central nitrogen methylation of a triamine linker) in a dimeric compound can enhance lysosomal localization and increase the specificity of CADs as anti-lysosomal agents.…”

Section: Discussionmentioning

confidence: 99%

A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles

et al. 2017

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Lysosomes serve dual roles in cancer metabolism, executing catabolic programs (i.e. autophagy and macropinocytosis), while promoting mTORC1-dependent anabolism. Antimalarial compounds such as chloroquine or quinacrine have been used as lysosomal inhibitors, but fail to inhibit mTOR signaling. Further, the molecular target of these agents has not been identified. We report a screen of novel dimeric antimalarials that identifies dimeric quinacrines (DQs) as potent anticancer compounds, which concurrently inhibit mTOR and autophagy. Central nitrogen methylation of the DQ linker enhances lysosomal localization and potency. An in situ photoaffinity pulldown identified palmitoyl-protein thioesterase 1 (PPT1) as the molecular target of DQ661. PPT1 inhibition concurrently impairs mTOR and lysosomal catabolism through the rapid accumulation of palmitoylated proteins. DQ661 inhibits the in vivo tumor growth of melanoma, pancreatic, and colorectal cancer mouse models and can be safely combined with chemotherapy. Thus, lysosome-directed PPT1 inhibitors represent a new approach to concurrently targeting mTORC1 and lysosomal catabolism in cancer.

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Amiodarone as an autophagy promoter reduces liver injury and enhances liver regeneration and survival in mice after partial hepatectomy

Cited by 55 publications

References 32 publications

Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system

Hepatocellular carcinoma–related cyclin D1 is selectively regulated by autophagy degradation system

Pharmacological modulators of autophagy activate a parallel noncanonical pathway driving unconventional LC3 lipidation

A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles

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