PHGDH drives 5-FU chemoresistance in colorectal cancer through the Hedgehog signaling
Abstract Background Phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in the de novo Serine synthesis pathway (SSP), a highly regulated pathway overexpressed in several tumors. Specifically, PHGDH expression is dynamically regulated during different stages of tumor progression, prom...
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2025-07-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03447-y |
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| author | Caterina Mancini Giulia Lori Gianluca Mattei Marta Iozzo Dayana Desideri Fabio Cianchi Laura Fortuna Federico Passagnoli Daniela Massi Filippo Ugolini Luca Messerini Salvatore Piscuoglio Antonio Pezone Francesca Magherini Alessio Biagioni Tiziano Lottini Demetra Zambardino Giuseppina Ivana Truglio Elena Petricci Alberto Magi Annarosa Arcangeli Luisa Maresca Barbara Stecca Erica Pranzini Maria Letizia Taddei |
| author_facet | Caterina Mancini Giulia Lori Gianluca Mattei Marta Iozzo Dayana Desideri Fabio Cianchi Laura Fortuna Federico Passagnoli Daniela Massi Filippo Ugolini Luca Messerini Salvatore Piscuoglio Antonio Pezone Francesca Magherini Alessio Biagioni Tiziano Lottini Demetra Zambardino Giuseppina Ivana Truglio Elena Petricci Alberto Magi Annarosa Arcangeli Luisa Maresca Barbara Stecca Erica Pranzini Maria Letizia Taddei |
| author_sort | Caterina Mancini |
| collection | DOAJ |
| description | Abstract Background Phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in the de novo Serine synthesis pathway (SSP), a highly regulated pathway overexpressed in several tumors. Specifically, PHGDH expression is dynamically regulated during different stages of tumor progression, promoting cancer aggressiveness. Previously, we demonstrated that high Serine (Ser) availability, obtained by increased exogenous uptake or increased PHGDH expression, supports 5-Fluorouracil (5-FU) resistance in colorectal cancer (CRC). Beyond its metabolic role in sustaining Ser biosynthesis, different “non-enzymatic roles” for PHGDH have recently been identified. The present study aims to investigate non-enzymatic mechanisms through which PHGDH regulates 5-FU response in CRC. Methods Overexpression and gene silencing approaches have been used to modulate PHGDH expression in human CRC cell lines to investigate the role of this enzyme in 5-FU cellular response. Identified mechanisms have been validated in selected 5-FU resistant cell lines, CRC patients-derived tumor tissue samples, and patients-derived 3D organoids. Transcriptomic analysis was performed on wild-type and PHGDH-silenced cell lines, allowing the identification of pathways responsible for PHGDH-mediated 5-FU resistance. The relevance of identified genes was validated in vitro and in vivo in a CRC xenograft model. Results PHGDH expression is highly variable among CRC tissues and patient-derived 3D organoids. A retrospective analysis of CRC patients highlighted a correlation between PHGDH expression and therapy response. Coherently, the modulation of PHGDH expression by gene silencing/overexpression affects 5-FU sensitivity in CRC cell lines. Transcriptomic analysis on CRC cell lines stably silenced for PHGDH evidenced down regulation in Hedgehog (HH) pathway. Accordingly, in vitro and in vivo studies demonstrated that the combined treatment of 5-FU and HH pathway inhibitors strongly hinders CRC cell survival and tumor growth in CRC xenograft models. Conclusions PHGDH sustains 5-FU resistance in CRC by mediating the upregulation of the HH signaling; targeting the here identified PHGDH-HH axis increases 5-FU susceptibility in different CRC models suggesting the 5-FU/HH-inhibitors combinatorial therapeutic strategy as a valid approach to counteract drug resistance in CRC. |
| format | Article |
| id | doaj-art-bdd2adf4f9394b30a5ac167d3e11f7dc |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
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| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-bdd2adf4f9394b30a5ac167d3e11f7dc2025-08-20T03:42:04ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-07-0144112110.1186/s13046-025-03447-yPHGDH drives 5-FU chemoresistance in colorectal cancer through the Hedgehog signalingCaterina Mancini0Giulia Lori1Gianluca Mattei2Marta Iozzo3Dayana Desideri4Fabio Cianchi5Laura Fortuna6Federico Passagnoli7Daniela Massi8Filippo Ugolini9Luca Messerini10Salvatore Piscuoglio11Antonio Pezone12Francesca Magherini13Alessio Biagioni14Tiziano Lottini15Demetra Zambardino16Giuseppina Ivana Truglio17Elena Petricci18Alberto Magi19Annarosa Arcangeli20Luisa Maresca21Barbara Stecca22Erica Pranzini23Maria Letizia Taddei24Department of Experimental and Clinical Medicine, University of FlorenceDepartment of Experimental and Clinical Medicine, University of FlorenceDepartment of Health Sciences Clinical Pharmacology and Oncology Unit, University of FlorenceDepartment of Experimental and Clinical Biomedical Sciences, University of FlorenceDepartment of Experimental and Clinical Medicine, University of FlorenceDepartment of Experimental and Clinical Medicine, University of FlorenceDepartment of Experimental and Clinical Medicine, University of FlorenceDepartment of Experimental and Clinical Medicine, University of FlorenceDepartment of Health Sciences, University of FlorenceDepartment of Health Sciences, University of FlorenceDepartment of Health Sciences, University of FlorenceIRCCS Humanitas Research HospitalDepartment of Biology, University of Naples “Federico II”Department of Experimental and Clinical Biomedical Sciences, University of FlorenceDepartment of Experimental and Clinical Biomedical Sciences, University of FlorenceDepartment of Experimental and Clinical Medicine, University of FlorenceDepartment of Biotechnology, Chemistry and Pharmacy, University of SienaDepartment of Biotechnology, Chemistry and Pharmacy, University of SienaDepartment of Biotechnology, Chemistry and Pharmacy, University of SienaDepartment of Information Engineering, University of FlorenceDepartment of Experimental and Clinical Medicine, University of FlorenceDepartment of Experimental and Clinical Biomedical Sciences, University of FlorenceCore Research Laboratory, ISPRODepartment of Experimental and Clinical Biomedical Sciences, University of FlorenceDepartment of Experimental and Clinical Medicine, University of FlorenceAbstract Background Phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in the de novo Serine synthesis pathway (SSP), a highly regulated pathway overexpressed in several tumors. Specifically, PHGDH expression is dynamically regulated during different stages of tumor progression, promoting cancer aggressiveness. Previously, we demonstrated that high Serine (Ser) availability, obtained by increased exogenous uptake or increased PHGDH expression, supports 5-Fluorouracil (5-FU) resistance in colorectal cancer (CRC). Beyond its metabolic role in sustaining Ser biosynthesis, different “non-enzymatic roles” for PHGDH have recently been identified. The present study aims to investigate non-enzymatic mechanisms through which PHGDH regulates 5-FU response in CRC. Methods Overexpression and gene silencing approaches have been used to modulate PHGDH expression in human CRC cell lines to investigate the role of this enzyme in 5-FU cellular response. Identified mechanisms have been validated in selected 5-FU resistant cell lines, CRC patients-derived tumor tissue samples, and patients-derived 3D organoids. Transcriptomic analysis was performed on wild-type and PHGDH-silenced cell lines, allowing the identification of pathways responsible for PHGDH-mediated 5-FU resistance. The relevance of identified genes was validated in vitro and in vivo in a CRC xenograft model. Results PHGDH expression is highly variable among CRC tissues and patient-derived 3D organoids. A retrospective analysis of CRC patients highlighted a correlation between PHGDH expression and therapy response. Coherently, the modulation of PHGDH expression by gene silencing/overexpression affects 5-FU sensitivity in CRC cell lines. Transcriptomic analysis on CRC cell lines stably silenced for PHGDH evidenced down regulation in Hedgehog (HH) pathway. Accordingly, in vitro and in vivo studies demonstrated that the combined treatment of 5-FU and HH pathway inhibitors strongly hinders CRC cell survival and tumor growth in CRC xenograft models. Conclusions PHGDH sustains 5-FU resistance in CRC by mediating the upregulation of the HH signaling; targeting the here identified PHGDH-HH axis increases 5-FU susceptibility in different CRC models suggesting the 5-FU/HH-inhibitors combinatorial therapeutic strategy as a valid approach to counteract drug resistance in CRC.https://doi.org/10.1186/s13046-025-03447-yPhosphoglycerate dehydrogenaseChemo-resistance5-FluorouracilColorectal cancerSerineStemness |
| spellingShingle | Caterina Mancini Giulia Lori Gianluca Mattei Marta Iozzo Dayana Desideri Fabio Cianchi Laura Fortuna Federico Passagnoli Daniela Massi Filippo Ugolini Luca Messerini Salvatore Piscuoglio Antonio Pezone Francesca Magherini Alessio Biagioni Tiziano Lottini Demetra Zambardino Giuseppina Ivana Truglio Elena Petricci Alberto Magi Annarosa Arcangeli Luisa Maresca Barbara Stecca Erica Pranzini Maria Letizia Taddei PHGDH drives 5-FU chemoresistance in colorectal cancer through the Hedgehog signaling Journal of Experimental & Clinical Cancer Research Phosphoglycerate dehydrogenase Chemo-resistance 5-Fluorouracil Colorectal cancer Serine Stemness |
| title | PHGDH drives 5-FU chemoresistance in colorectal cancer through the Hedgehog signaling |
| title_full | PHGDH drives 5-FU chemoresistance in colorectal cancer through the Hedgehog signaling |
| title_fullStr | PHGDH drives 5-FU chemoresistance in colorectal cancer through the Hedgehog signaling |
| title_full_unstemmed | PHGDH drives 5-FU chemoresistance in colorectal cancer through the Hedgehog signaling |
| title_short | PHGDH drives 5-FU chemoresistance in colorectal cancer through the Hedgehog signaling |
| title_sort | phgdh drives 5 fu chemoresistance in colorectal cancer through the hedgehog signaling |
| topic | Phosphoglycerate dehydrogenase Chemo-resistance 5-Fluorouracil Colorectal cancer Serine Stemness |
| url | https://doi.org/10.1186/s13046-025-03447-y |
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