Butyrate Inhibits Colorectal Cancer Cell Proliferation through Autophagy Degradation of β-Catenin Regardless of <i>APC</i> and β-Catenin Mutational Status
Colorectal cancer (CRC) pathogenesis is mainly driven by alterations in WNT signaling, which results in altered transcriptional activity of β-Catenin. Mutations in <i>APC</i> (Adenomatous Polyposis Coli) are reflected in β-Catenin hyperactivation and loss of proliferation control. Certai...
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| Format: | Article |
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MDPI AG
2022-05-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/10/5/1131 |
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| author | Beatrice Garavaglia Letizia Vallino Alessandra Ferraresi Andrea Esposito Amreen Salwa Chiara Vidoni Sergio Gentilli Ciro Isidoro |
| author_facet | Beatrice Garavaglia Letizia Vallino Alessandra Ferraresi Andrea Esposito Amreen Salwa Chiara Vidoni Sergio Gentilli Ciro Isidoro |
| author_sort | Beatrice Garavaglia |
| collection | DOAJ |
| description | Colorectal cancer (CRC) pathogenesis is mainly driven by alterations in WNT signaling, which results in altered transcriptional activity of β-Catenin. Mutations in <i>APC</i> (Adenomatous Polyposis Coli) are reflected in β-Catenin hyperactivation and loss of proliferation control. Certain intestinal bacteria metabolites have shown the ability to limit CRC cell proliferation and CRC pathogenesis. Here, we investigated the molecular mechanism underlying the anti-proliferative activity of butyrate, a microbiota-derived short chain fatty acid, in two CRC cell lines, namely HCT116 and SW620, which bear a mutation in β-Catenin and <i>APC</i>, respectively. In particular, we focused on autophagy, a lysosome-dependent degradation pathway, which was shown to control intestinal tissue homeostasis. Butyrate reduced CRC cell proliferation, as witnessed by the downregulation of proliferation markers. TCGA bioinformatic transcriptomic analysis of <i>CTNNB1</i> (β-Catenin) gene correlation in CRC patients showed that β-Catenin negatively correlates with the autophagy gene <i>ATG4D</i>. In CRC cells, regardless of the mutational state of <i>APC</i> or β-Catenin genes, butyrate caused the autophagy-mediated degradation of β-Catenin; thus, preventing its transcriptional activity. Autophagy gene silencing restored β-Catenin levels, allowing it to translocate into the nucleus to promote the expression of downstream genes associated with cancer cell proliferation. CRC-affected patients show driver mutations in the WNT pathway; thus, targeting its crucial effector may be a promising therapeutic strategy in CRC treatment; for instance, by using <i>ad hoc</i> probiotics that stimulate autophagy. |
| first_indexed | 2024-03-10T03:16:36Z |
| format | Article |
| id | doaj.art-7f29eb94e2a84e188c99aa66f156981f |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T03:16:36Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-7f29eb94e2a84e188c99aa66f156981f2023-11-23T10:11:30ZengMDPI AGBiomedicines2227-90592022-05-01105113110.3390/biomedicines10051131Butyrate Inhibits Colorectal Cancer Cell Proliferation through Autophagy Degradation of β-Catenin Regardless of <i>APC</i> and β-Catenin Mutational StatusBeatrice Garavaglia0Letizia Vallino1Alessandra Ferraresi2Andrea Esposito3Amreen Salwa4Chiara Vidoni5Sergio Gentilli6Ciro Isidoro7Laboratory of Molecular Pathology, Department of Health Sciences, University of Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, ItalyLaboratory of Molecular Pathology, Department of Health Sciences, University of Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, ItalyLaboratory of Molecular Pathology, Department of Health Sciences, University of Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, ItalyLaboratory of Molecular Pathology, Department of Health Sciences, University of Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, ItalyLaboratory of Molecular Pathology, Department of Health Sciences, University of Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, ItalyLaboratory of Molecular Pathology, Department of Health Sciences, University of Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, ItalyDepartment of Health Sciences, Division of General Surgery, Maggiore della Carità Hospital, University of Piemonte Orientale, 28100 Novara, ItalyLaboratory of Molecular Pathology, Department of Health Sciences, University of Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, ItalyColorectal cancer (CRC) pathogenesis is mainly driven by alterations in WNT signaling, which results in altered transcriptional activity of β-Catenin. Mutations in <i>APC</i> (Adenomatous Polyposis Coli) are reflected in β-Catenin hyperactivation and loss of proliferation control. Certain intestinal bacteria metabolites have shown the ability to limit CRC cell proliferation and CRC pathogenesis. Here, we investigated the molecular mechanism underlying the anti-proliferative activity of butyrate, a microbiota-derived short chain fatty acid, in two CRC cell lines, namely HCT116 and SW620, which bear a mutation in β-Catenin and <i>APC</i>, respectively. In particular, we focused on autophagy, a lysosome-dependent degradation pathway, which was shown to control intestinal tissue homeostasis. Butyrate reduced CRC cell proliferation, as witnessed by the downregulation of proliferation markers. TCGA bioinformatic transcriptomic analysis of <i>CTNNB1</i> (β-Catenin) gene correlation in CRC patients showed that β-Catenin negatively correlates with the autophagy gene <i>ATG4D</i>. In CRC cells, regardless of the mutational state of <i>APC</i> or β-Catenin genes, butyrate caused the autophagy-mediated degradation of β-Catenin; thus, preventing its transcriptional activity. Autophagy gene silencing restored β-Catenin levels, allowing it to translocate into the nucleus to promote the expression of downstream genes associated with cancer cell proliferation. CRC-affected patients show driver mutations in the WNT pathway; thus, targeting its crucial effector may be a promising therapeutic strategy in CRC treatment; for instance, by using <i>ad hoc</i> probiotics that stimulate autophagy.https://www.mdpi.com/2227-9059/10/5/1131short chain fatty acid (SCFA)cell proliferationWNT signaling pathwaymicrobiotaautophagyLC3 |
| spellingShingle | Beatrice Garavaglia Letizia Vallino Alessandra Ferraresi Andrea Esposito Amreen Salwa Chiara Vidoni Sergio Gentilli Ciro Isidoro Butyrate Inhibits Colorectal Cancer Cell Proliferation through Autophagy Degradation of β-Catenin Regardless of <i>APC</i> and β-Catenin Mutational Status Biomedicines short chain fatty acid (SCFA) cell proliferation WNT signaling pathway microbiota autophagy LC3 |
| title | Butyrate Inhibits Colorectal Cancer Cell Proliferation through Autophagy Degradation of β-Catenin Regardless of <i>APC</i> and β-Catenin Mutational Status |
| title_full | Butyrate Inhibits Colorectal Cancer Cell Proliferation through Autophagy Degradation of β-Catenin Regardless of <i>APC</i> and β-Catenin Mutational Status |
| title_fullStr | Butyrate Inhibits Colorectal Cancer Cell Proliferation through Autophagy Degradation of β-Catenin Regardless of <i>APC</i> and β-Catenin Mutational Status |
| title_full_unstemmed | Butyrate Inhibits Colorectal Cancer Cell Proliferation through Autophagy Degradation of β-Catenin Regardless of <i>APC</i> and β-Catenin Mutational Status |
| title_short | Butyrate Inhibits Colorectal Cancer Cell Proliferation through Autophagy Degradation of β-Catenin Regardless of <i>APC</i> and β-Catenin Mutational Status |
| title_sort | butyrate inhibits colorectal cancer cell proliferation through autophagy degradation of β catenin regardless of i apc i and β catenin mutational status |
| topic | short chain fatty acid (SCFA) cell proliferation WNT signaling pathway microbiota autophagy LC3 |
| url | https://www.mdpi.com/2227-9059/10/5/1131 |
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