Simultaneous activation and blockade of autophagy to fight hepatocellular carcinoma
ABSTRACTAutophagy is considered a target for cancer treatment, although few compounds manipulating this process have been added to the anticancer arsenal in humans. Pharmacological manipulation of autophagy has therefore been considered in the treatment and chemosensitization of hepatocellular carci...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Autophagy Reports |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/27694127.2024.2326241 |
| _version_ | 1797235646411046912 |
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| author | Hala Shalhoub Patrick Gonzalez Alexandre Dos Santos Julie Guillermet-Guibert Nicolas Moniaux Nicolas Dupont Jamila Faivre |
| author_facet | Hala Shalhoub Patrick Gonzalez Alexandre Dos Santos Julie Guillermet-Guibert Nicolas Moniaux Nicolas Dupont Jamila Faivre |
| author_sort | Hala Shalhoub |
| collection | DOAJ |
| description | ABSTRACTAutophagy is considered a target for cancer treatment, although few compounds manipulating this process have been added to the anticancer arsenal in humans. Pharmacological manipulation of autophagy has therefore been considered in the treatment and chemosensitization of hepatocellular carcinoma (HCC), a heterogeneous malignancy that remains difficult to treat (limited impact of genomic discoveries for the implementation of personalized precision medicine). We analyzed the autophagy marker proteins p62 and LC3 in paired tumor and adjacent cirrhotic non-tumor tissues of human HCC. We show strong variability in p62 and LC3-II levels between tumor parts of different HCC patients and between tumor and non-tumor HCC in the same patient, suggesting heterogeneity in autophagy flux. This diversity in flux led us to consider a non-personalized method of autophagy targeting, combining simultaneous activation and blockade of autophagy, which could, in theory, benefit a substantial number of HCC patients, irrespective of tumor autophagic flux. We show that the combination of sodium butyrate (NaB, autophagy inducer) and chloroquine (CQ, autophagy blocker) has a marked and synergistic cytotoxic effect in vitro on all human liver cancer cell lines studied, compared with the cellular effect of each product separately, and with no deleterious effect on normal hepatocytes in culture. Cancer cell death was associated with accumulation of autophagosomes, induction of lysosome membrane permeabilization and increased oxidative stress. Our results suggest that simultaneous activation and blockade of autophagy may be a valuable approach against HCC, and that microbiota-derived products improve the sensitivity of HCC cells to antitumor agents.Abbreviations AV: annexin V; CI: combination index; CTSB: Cathepsin B; CTSD: Cathepsin D; CTSF: Cathepsin F; CQ: chloroquine; DEN: N-diethylnitrosamine; DMEM: Dulbecco’s modified eagle medium; FBS: fetal bovine serum; FSC: forward scatter; GNS: N-acetylglucosamine-6-sulfatase; HCC: hepatocellular carcinoma; HDACi: histone deacetylase inhibitor; HCQ: hydroxychloroquine; LMP: lysosomal membrane permeabilization; LAMP1: lysosome-associated membrane protein; LIPA: Lysosomal acid lipase; LSR: Lysosomal staining cells; MAP1LC3A: microtubule associated protein 1 light chain 3 alpha; NaB: sodium butyrate; NASH: non-alcoholic steatohepatitis; NRF2: nuclear factor erythroid 2–related factor 2; PI: propidium iodide; PMSF: phenylmethanesulfonyl fluoride; ROS: reactive oxygen species; SCARB2: Scavenger receptor class B member 2; SQSTM1/p62: sequestosome 1; SMPD1: Sphingomyelin phosphodiesterase 1; SSC: side scatter; TFEB: transcription factor EB. |
| first_indexed | 2024-04-24T16:51:16Z |
| format | Article |
| id | doaj.art-fbad5d5979cb4a2c9071370532453378 |
| institution | Directory Open Access Journal |
| issn | 2769-4127 |
| language | English |
| last_indexed | 2024-04-24T16:51:16Z |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Autophagy Reports |
| spelling | doaj.art-fbad5d5979cb4a2c90713705324533782024-03-29T03:32:14ZengTaylor & Francis GroupAutophagy Reports2769-41272024-12-013110.1080/27694127.2024.2326241Simultaneous activation and blockade of autophagy to fight hepatocellular carcinomaHala Shalhoub0Patrick Gonzalez1Alexandre Dos Santos2Julie Guillermet-Guibert3Nicolas Moniaux4Nicolas Dupont5Jamila Faivre6INSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, Villejuif, FranceINSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, Villejuif, FranceINSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, Villejuif, FranceCentre de Recherches en Cancérologie de Toulouse (CRCT), Inserm U1037, CNRS, Université Toulouse III, Toulouse, FranceINSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, Villejuif, FranceInstitut Necker Enfants-Malades (INEM), INSERM U1151/CNRS UMR 8253, Université de Paris, Paris, FranceINSERM, U1193, Paul-Brousse University Hospital, Hepatobiliary Centre, Villejuif, FranceABSTRACTAutophagy is considered a target for cancer treatment, although few compounds manipulating this process have been added to the anticancer arsenal in humans. Pharmacological manipulation of autophagy has therefore been considered in the treatment and chemosensitization of hepatocellular carcinoma (HCC), a heterogeneous malignancy that remains difficult to treat (limited impact of genomic discoveries for the implementation of personalized precision medicine). We analyzed the autophagy marker proteins p62 and LC3 in paired tumor and adjacent cirrhotic non-tumor tissues of human HCC. We show strong variability in p62 and LC3-II levels between tumor parts of different HCC patients and between tumor and non-tumor HCC in the same patient, suggesting heterogeneity in autophagy flux. This diversity in flux led us to consider a non-personalized method of autophagy targeting, combining simultaneous activation and blockade of autophagy, which could, in theory, benefit a substantial number of HCC patients, irrespective of tumor autophagic flux. We show that the combination of sodium butyrate (NaB, autophagy inducer) and chloroquine (CQ, autophagy blocker) has a marked and synergistic cytotoxic effect in vitro on all human liver cancer cell lines studied, compared with the cellular effect of each product separately, and with no deleterious effect on normal hepatocytes in culture. Cancer cell death was associated with accumulation of autophagosomes, induction of lysosome membrane permeabilization and increased oxidative stress. Our results suggest that simultaneous activation and blockade of autophagy may be a valuable approach against HCC, and that microbiota-derived products improve the sensitivity of HCC cells to antitumor agents.Abbreviations AV: annexin V; CI: combination index; CTSB: Cathepsin B; CTSD: Cathepsin D; CTSF: Cathepsin F; CQ: chloroquine; DEN: N-diethylnitrosamine; DMEM: Dulbecco’s modified eagle medium; FBS: fetal bovine serum; FSC: forward scatter; GNS: N-acetylglucosamine-6-sulfatase; HCC: hepatocellular carcinoma; HDACi: histone deacetylase inhibitor; HCQ: hydroxychloroquine; LMP: lysosomal membrane permeabilization; LAMP1: lysosome-associated membrane protein; LIPA: Lysosomal acid lipase; LSR: Lysosomal staining cells; MAP1LC3A: microtubule associated protein 1 light chain 3 alpha; NaB: sodium butyrate; NASH: non-alcoholic steatohepatitis; NRF2: nuclear factor erythroid 2–related factor 2; PI: propidium iodide; PMSF: phenylmethanesulfonyl fluoride; ROS: reactive oxygen species; SCARB2: Scavenger receptor class B member 2; SQSTM1/p62: sequestosome 1; SMPD1: Sphingomyelin phosphodiesterase 1; SSC: side scatter; TFEB: transcription factor EB.https://www.tandfonline.com/doi/10.1080/27694127.2024.2326241Liver cancercholangiocarcinomamicrobial metabolitebutyratechloroquinetherapy |
| spellingShingle | Hala Shalhoub Patrick Gonzalez Alexandre Dos Santos Julie Guillermet-Guibert Nicolas Moniaux Nicolas Dupont Jamila Faivre Simultaneous activation and blockade of autophagy to fight hepatocellular carcinoma Autophagy Reports Liver cancer cholangiocarcinoma microbial metabolite butyrate chloroquine therapy |
| title | Simultaneous activation and blockade of autophagy to fight hepatocellular carcinoma |
| title_full | Simultaneous activation and blockade of autophagy to fight hepatocellular carcinoma |
| title_fullStr | Simultaneous activation and blockade of autophagy to fight hepatocellular carcinoma |
| title_full_unstemmed | Simultaneous activation and blockade of autophagy to fight hepatocellular carcinoma |
| title_short | Simultaneous activation and blockade of autophagy to fight hepatocellular carcinoma |
| title_sort | simultaneous activation and blockade of autophagy to fight hepatocellular carcinoma |
| topic | Liver cancer cholangiocarcinoma microbial metabolite butyrate chloroquine therapy |
| url | https://www.tandfonline.com/doi/10.1080/27694127.2024.2326241 |
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