A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors

Akin, Debra; Wang, S. Keisin; Habibzadegah-Tari, Pouran; Law, Brian K.; Ostrov, David A.; Li, Min; Yin, Xiao Ming; Kim, Jae Sung; Horenstein, Nicole A.; Dunn, William A.

doi:10.4161/auto.32229

Cited by 210 publications

(211 citation statements)

References 65 publications

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“…Our results are consistent with the reports on the role of ATG4B in chemotherapy-induced protective autophagy in cancer cells. 16,17 Interestingly, a dose of 400 ng/ml THP downregulated the expression of several autophagy-related genes including ATG5, ATG10, BECN1, ATG7, and ATG16L1 at mRNA levels but not the protein levels. The reason(s) may be due to THP-triggered alteration of mRNA translation and protein degradation.…”

Section: Discussionmentioning

confidence: 99%

“…13,14 Recent studies have shown that ATG4B plays an important role in cancer therapy through modulating the level of autophagy in a context-dependent manner. 15 Targeting ATG4B can also enhance the chemotherapeutic effect in several cancer cells such as CML, 16 osteosarcoma tumor 17 and breast cancer. 18 However, whether ATG4B plays a role in the chemotherapy of cervical cancer still needs to be investigated.…”

Section: Introductionmentioning

confidence: 99%

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Targeting the MIR34C-5p-ATG4B-autophagy axis enhances the sensitivity of cervical cancer cells to pirarubicin

Yan

et al. 2016

Autophagy

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Pirarubicin (THP) is a newer generation anthracycline anticancer drug. In the clinic, THP and THP-based combination therapies have been demonstrated to be effective against various tumors without severe side effects. However, previous clinical studies have shown that most patients with cervical cancer are not sensitive to THP treatment, and the associated mechanisms are not clear. Consistent with the clinical study, we confirmed that cervical cancer cells were resistant to THP in vitro and in vivo. Our data demonstrated that THP induced a protective macroautophagy/autophagy response in cervical cancer cells, and suppression of this autophagy dramatically enhanced the cytotoxicity of THP. By scanning the mRNA level change of autophagy-related genes, we found that the upregulation of ATG4B (autophagyrelated 4B cysteine peptidase) plays an important role in THP-induced autophagy. Moreover, THP increased the mRNA level of ATG4B in cervical cancer cells by promoting mRNA stability without influencing its transcription. Furthermore, THP triggered a downregulation of MIR34C-5p, which was associated with the upregulation of ATG4B and autophagy induction. Overexpression of MIR34C-5p significantly decreased the level of ATG4B and attenuated autophagy, accompanied by enhanced cell death and apoptosis in THP-treated cervical cancer cells. These results for the first time reveal the presence of a MIR34C-5p-ATG4B-autophagy signaling axis in THP-treated cervical cancer cells in vitro and in vivo, and the axis, at least partially, accounts for the THP nonsensitivity in cervical cancer patients. This study may provide a new insight for improving the chemotherapeutic effect of THP, which may be beneficial to the further clinical application of THP in cervical cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting the MIR34C-5p-ATG4B-autophagy axis enhances the sensitivity of cervical cancer cells to pirarubicin

Yan

et al. 2016

Autophagy

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“…In silico approaches and in vitro studies identified an Atg4B inhibitor with low potency, which blocked autophagy and promoted tumor cell death (Akin et al 2014.). In vitro assays for inhibitors of ATG4B protease activity have been developed with the potential to generate highly selective and potent inhibitors (Vezenkov et al 2015;Xu et al 2016).…”

Section: Atg4 Inhibitorsmentioning

confidence: 99%

Recent insights into the function of autophagy in cancer

2016

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Macroautophagy (referred to here as autophagy) is induced by starvation to capture and degrade intracellular proteins and organelles in lysosomes, which recycles intracellular components to sustain metabolism and survival. Autophagy also plays a major homeostatic role in controlling protein and organelle quality and quantity. Dysfunctional autophagy contributes to many diseases. In cancer, autophagy can be neutral, tumor-suppressive, or tumorpromoting in different contexts. Large-scale genomic analysis of human cancers indicates that the loss or mutation of core autophagy genes is uncommon, whereas oncogenic events that activate autophagy and lysosomal biogenesis have been identified. Autophagic flux, however, is difficult to measure in human tumor samples, making functional assessment of autophagy problematic in a clinical setting. Autophagy impacts cellular metabolism, the proteome, and organelle numbers and quality, which alter cell functions in diverse ways. Moreover, autophagy influences the interaction between the tumor and the host by promoting stress adaptation and suppressing activation of innate and adaptive immune responses. Additionally, autophagy can promote a cross-talk between the tumor and the stroma, which can support tumor growth, particularly in a nutrient-limited microenvironment. Thus, the role of autophagy in cancer is determined by nutrient availability, microenvironment stress, and the presence of an immune system. Here we discuss recent developments in the role of autophagy in cancer, in particular how autophagy can promote cancer through suppressing p53 and preventing energy crisis, cell death, senescence, and an anti-tumor immune response.The core autophagy machinery is encoded by autophagyrelated (ATG) genes, of which there are now >30 (Ktistakis and Tooze 2016). These genes and their protein products are regulated by numerous upstream signals, including nutrient availability, stressors, defective organelles, and pathogenic conditions. ATG gene products control the formation of the hallmark double-membrane vesicle, the autophagosome. Other genes encode cargo receptors that direct the cargo to the forming autophagosome. Control of the trafficking machinery then orchestrates fusion of the cargo-laden autophagosomes with lysosomes. Degradative enzymes, contributed by lysosomes, break down the cargo, and the products are exported into the cytoplasm, where they are recycled into metabolic and biosynthetic pathways (Rabinowitz and White 2010;Guo et al. 2016). Under normal nutrient conditions, autophagy functions at a constitutive, low basal level to maintain protein and organelle quality, quantity, and functionality. The ATG genes and autophagy are dramatically induced by starvation and other stressors, which enable cellular and organismal survival. Up-regulation of autophagy is a means to survive nutrient stress, which is conserved from yeast to mammals. More recently, there is a growing appreciation of the role played by ATG genes in modulating intracellular trafficking, endocytosis, exoc...

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“…A very recent publication has given strong direct evidence for the potential of inhibitors of ATG4B in treating cancer. Atkin et al 27 identified a small molecule ATG4B inhibitor with moderate potency (IC 50 51 lM as tested in an assay developed by Li et al) 28 from in silico docking of small molecules from the NCI library into the ATG4B active site. In spite of its rather low potency, the authors showed that the compound, NSC185058, suppressed formation of autophagic vesicles in starved cells, suppressed activation and lipidation of LC3 and, most significantly, suppressed autophagic markers in livers of fasted mice, and suppressed autophagy and growth of osteosarcoma tumors both in vitro and in vivo in immunodeficient mice.…”

Section: Introductionmentioning

confidence: 99%

Development of fluorescent peptide substrates and assays for the key autophagy-initiating cysteine protease enzyme, ATG4B

Vezenkov

Honson

Kumar

et al. 2015

Bioorganic & Medicinal Chemistry

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A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors

Cited by 210 publications

References 65 publications

Targeting the MIR34C-5p-ATG4B-autophagy axis enhances the sensitivity of cervical cancer cells to pirarubicin

Targeting the MIR34C-5p-ATG4B-autophagy axis enhances the sensitivity of cervical cancer cells to pirarubicin

Recent insights into the function of autophagy in cancer

Development of fluorescent peptide substrates and assays for the key autophagy-initiating cysteine protease enzyme, ATG4B

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