p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming

Saito, Tetsuya; Ichimura, Yoshinobu; Taguchi, Keiko; Suzuki, Takafumi; Mizushima, Tsunehiro; Takagi, Kenji; Hirose, Yuki; Nagahashi, Masayuki; Iso, Tetsuro; Fukutomi, Toshiaki; Ohishi, Maki; Endo, Keiko; Uemura, Takefumi; Nishito, Yasumasa; Okuda, Shujiro; Obata, Miki; Kouno, Tsuguka; Imamura, Riyo; Tada, Yukio; Obata, Rika; Yasuda, Daisuke; Takahashi, Kyoko; Fujimura, Tsutomu; Pi, Jingbo; Lee, Myung-Shik; Ueno, Takashi; Ohe, Tomoyuki; Mashino, Tadahiko; Wakai, Toshifumi; Kojima, Hirotatsu; Okabe, Takayoshi; Nagano, Tetsuo; Motohashi, Hozumi; Waguri, Satoshi; Soga, Tomoyoshi; Yamamoto, Masayuki; Tanaka, Keiji; Komatsu, Masaaki

doi:10.1038/ncomms12030

Cited by 277 publications

(317 citation statements)

References 69 publications

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“…To further increase the antitumor effects of targeting CD47 by SIRPaD1-Fc in NSCLC, we examined probable mechanisms of resistance to SIRPaD1-Fc treatment. Autophagy, an important mechanism of tumor therapy resistance, is increasingly regarded as a target for synergistic antitumor therapy (41)(42)(43). We report here that targeting CD47 could trigger autophagy in NSCLC cells.…”

Section: Discussionmentioning

confidence: 80%

Targeting CD47 and Autophagy Elicited Enhanced Antitumor Effects in Non–Small Cell Lung Cancer

Zhang

Fan

Wang

et al. 2017

Cancer Immunology Research

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CD47-specific antibodies and fusion proteins that block CD47-SIRPa signaling are employed as antitumor agents for several cancers. Here, we investigated the synergistic antitumor effect of simultaneously targeting CD47 and autophagy in nonsmall cell lung cancer (NSCLC). SIRPaD1-Fc, a novel CD47-targeting fusion protein, was generated and was found to increase the phagocytic and cytotoxic activities of macrophages against NSCLC cells. During this process, autophagy was markedly triggered, which was characterized by the three main stages of autophagic flux, including formation and accumulation of autophagosomes, fusion of autophagosomes with lysosomes, and degradation of autophagosomes in lysosomes. Meanwhile, reactive oxygen species and inactivation of mTOR were shown to be involved in autophagy initiation in SIRPaD1-Fc-treated cells, indicating a probable mechanism for autophagy activation after targeting CD47 by SIRPaD1-Fc. Inhibition of autophagy enhanced macrophage-mediated phagocytosis and cytotoxicity against SIRPaD1-Fc-treated NSCLC cells. In addition, simultaneously targeting both CD47 and autophagy in NSCLC xenograft models elicited enhanced antitumor effects, with recruitment of macrophages, activated caspase-3, and overproduction of ROS at the tumor site. Our data elucidated the cytoprotective role of autophagy in CD47-targeted therapy and highlighted the potential approach for NSCLC treatment by simultaneously targeting CD47 and autophagy.

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Section: Discussionmentioning

confidence: 80%

Targeting CD47 and Autophagy Elicited Enhanced Antitumor Effects in Non–Small Cell Lung Cancer

Zhang

Fan

Wang

et al. 2017

Cancer Immunology Research

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“…Phosphorylation of p62 at S349 activates NRF2 and directs glucose metabolism to the glucuronate pathway and glutamine metabolism to glutathione synthesis (67). These changes make HCC cells resistant to anticancer drugs and enhance their proliferation ability.…”

Section: Metabolic Reprogramming In Cancermentioning

confidence: 99%

The KEAP1–NRF2 System in Cancer

2017

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Cancer cells first adapt to the microenvironment and then propagate. Mutations in tumor suppressor genes or oncogenes are frequently found in cancer cells. Comprehensive genomic analyses have identified somatic mutations and other alterations in the KEAP1 or NRF2 genes and in well-known tumor suppressor genes or oncogenes, such as TP53, CDKN2A, PTEN, and PIK3CA, in various types of cancer. Aberrant NRF2 activation in cancer cells occurs through somatic mutations in the KEAP1 or NRF2 gene as well as through other mechanisms that disrupt the binding of KEAP1 to NRF2. Unregulated NRF2 confers on cancer cells high-level resistance to anticancer drugs and reactive oxygen species (ROS) and directs cancer cells toward metabolic reprogramming. Therefore, NRF2 has been studied as a therapeutic target molecule in cancer. Two strategies have been used to target NRF2 via therapeutic drugs: inhibition of NRF2 and induction of NRF2. NRF2 inhibitors may be effective against NRF2-addicted cancer cells in which NRF2 is aberrantly activated. These inhibitors have not yet been established as NRF2-targeted anticancer drugs for the treatment of human cancers. Diagnosis of NRF2 activation could facilitate the use of NRF2 inhibitors for the treatment of patients with NRF2-addicted cancers. Conversely, NRF2 inducers have been used or are being developed for non-cancer diseases. In addition, NRF2 inducers may be useful for cancer chemotherapy in combination with conventional anticancer agents or even NRF2 inhibitors.

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“…In multiple physiologically relevant HCC mouse models, p62 is necessary for the activation of mTORC1 in HCCs driven by TSC2 deficiency (Umemura et al 2016). A role for p62 in promoting NFR2 activation and HCC has also been identified (Saito et al 2016). Adenovirus-mediated overexpression of p62 in hepatocytes in vivo in the absence of any other oncogenic stimuli drives HCC through the activation of mTORC1 in a manner that is independent of p62's role as a cargo receptor in autophagy.…”

Section: Regulation Of Core Autophagy Genes and Cargo Receptors In Camentioning

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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p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming

Cited by 277 publications

References 69 publications

Targeting CD47 and Autophagy Elicited Enhanced Antitumor Effects in Non–Small Cell Lung Cancer

Targeting CD47 and Autophagy Elicited Enhanced Antitumor Effects in Non–Small Cell Lung Cancer

The KEAP1–NRF2 System in Cancer

Recent insights into the function of autophagy in cancer

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