Role of Oral Bacteria in Mediating Gemcitabine Resistance in Pancreatic Cancer
Oral microbiota have been implicated in pancreatic ductal adenocarcinoma (PDAC) and may contribute to chemotherapy resistance. While previous studies attributed bacteria-induced resistance to indirect host modulation, recent findings suggest a direct mechanism. <i>Escherichia coli</i> ex...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-07-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/15/7/1018 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850078209649934336 |
|---|---|
| author | Geng Xu Yaling Jiang Chen Sun Bernd W. Brandt Kamran Nazmi Luca Morelli Giulia Lencioni Elisa Giovannetti Dongmei Deng |
| author_facet | Geng Xu Yaling Jiang Chen Sun Bernd W. Brandt Kamran Nazmi Luca Morelli Giulia Lencioni Elisa Giovannetti Dongmei Deng |
| author_sort | Geng Xu |
| collection | DOAJ |
| description | Oral microbiota have been implicated in pancreatic ductal adenocarcinoma (PDAC) and may contribute to chemotherapy resistance. While previous studies attributed bacteria-induced resistance to indirect host modulation, recent findings suggest a direct mechanism. <i>Escherichia coli</i> expressing long-form cytidine deaminase (CDD<sub>L</sub>) can degrade gemcitabine, a chemotherapeutic agent, into a non-toxic form, leading to resistance. In contrast, bacteria carrying short form (CDD<sub>S</sub>) or lacking CDD did not induce resistance. This study investigates whether oral bacteria can cause gemcitabine resistance in PDAC cells through CDD-mediated degradation. Oral microbes associated with PDAC were selected based on CDD isoforms: <i>Aggregatibacter actinomycetemcomitans</i> carrying CDD<sub>L</sub>, <i>Enterococcus faecalis</i>, <i>Streptococcus mutans</i>, <i>Porphyromonas gingivalis</i>, all carrying CDD<sub>S</sub>, and <i>Fusobacterium nucleatum</i> lacking CDD. The selected microbes, along with wild-type and CDD-deficient <i>E. coli</i>, were co-incubated with gemcitabine to assess its degradation and PDAC cell proliferation. <i>A. actinomycetemcomitans</i> fully degraded gemcitabine and induced resistance. Surprisingly, CDD<sub>S</sub>-expressing oral bacteria partially degraded gemcitabine in a strain-dependent manner. Expressing either CDD<sub>L</sub> or CDD<sub>S</sub> in CDD-deficient <i>E. coli</i> resulted in equivalent gemcitabine degradation and resistance, indicating that CDD function is independent of isoform length. These findings highlight the role of oral bacteria in gemcitabine resistance and the need for strategies to mitigate microbial-driven resistance in PDAC treatment. |
| format | Article |
| id | doaj-art-ddd0a4fb11b040418ec7e57f0b8674fb |
| institution | DOAJ |
| issn | 2218-273X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj-art-ddd0a4fb11b040418ec7e57f0b8674fb2025-08-20T02:45:37ZengMDPI AGBiomolecules2218-273X2025-07-01157101810.3390/biom15071018Role of Oral Bacteria in Mediating Gemcitabine Resistance in Pancreatic CancerGeng Xu0Yaling Jiang1Chen Sun2Bernd W. Brandt3Kamran Nazmi4Luca Morelli5Giulia Lencioni6Elisa Giovannetti7Dongmei Deng8Department of Preventive Dentistry, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, 1081 LA Amsterdam, The NetherlandsDepartment of Preventive Dentistry, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, 1081 LA Amsterdam, The NetherlandsDepartment of Preventive Dentistry, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, 1081 LA Amsterdam, The NetherlandsDepartment of Preventive Dentistry, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, 1081 LA Amsterdam, The NetherlandsDepartment of Oral Biochemistry, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, 1081 LA Amsterdam, The NetherlandsGeneral Surgery Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 43, 56126 Pisa, ItalyFondazione Pisana per la Scienza, San Giuliano Terme, 13, 56017 Pisa, ItalyDepartment of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Amsterdam, 1081 HV Amsterdam, The NetherlandsDepartment of Preventive Dentistry, Academic Center for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, 1081 LA Amsterdam, The NetherlandsOral microbiota have been implicated in pancreatic ductal adenocarcinoma (PDAC) and may contribute to chemotherapy resistance. While previous studies attributed bacteria-induced resistance to indirect host modulation, recent findings suggest a direct mechanism. <i>Escherichia coli</i> expressing long-form cytidine deaminase (CDD<sub>L</sub>) can degrade gemcitabine, a chemotherapeutic agent, into a non-toxic form, leading to resistance. In contrast, bacteria carrying short form (CDD<sub>S</sub>) or lacking CDD did not induce resistance. This study investigates whether oral bacteria can cause gemcitabine resistance in PDAC cells through CDD-mediated degradation. Oral microbes associated with PDAC were selected based on CDD isoforms: <i>Aggregatibacter actinomycetemcomitans</i> carrying CDD<sub>L</sub>, <i>Enterococcus faecalis</i>, <i>Streptococcus mutans</i>, <i>Porphyromonas gingivalis</i>, all carrying CDD<sub>S</sub>, and <i>Fusobacterium nucleatum</i> lacking CDD. The selected microbes, along with wild-type and CDD-deficient <i>E. coli</i>, were co-incubated with gemcitabine to assess its degradation and PDAC cell proliferation. <i>A. actinomycetemcomitans</i> fully degraded gemcitabine and induced resistance. Surprisingly, CDD<sub>S</sub>-expressing oral bacteria partially degraded gemcitabine in a strain-dependent manner. Expressing either CDD<sub>L</sub> or CDD<sub>S</sub> in CDD-deficient <i>E. coli</i> resulted in equivalent gemcitabine degradation and resistance, indicating that CDD function is independent of isoform length. These findings highlight the role of oral bacteria in gemcitabine resistance and the need for strategies to mitigate microbial-driven resistance in PDAC treatment.https://www.mdpi.com/2218-273X/15/7/1018pancreatic cancergemcitabinecytidine deaminaseHPLCdrug resistancehost microbial interactions |
| spellingShingle | Geng Xu Yaling Jiang Chen Sun Bernd W. Brandt Kamran Nazmi Luca Morelli Giulia Lencioni Elisa Giovannetti Dongmei Deng Role of Oral Bacteria in Mediating Gemcitabine Resistance in Pancreatic Cancer Biomolecules pancreatic cancer gemcitabine cytidine deaminase HPLC drug resistance host microbial interactions |
| title | Role of Oral Bacteria in Mediating Gemcitabine Resistance in Pancreatic Cancer |
| title_full | Role of Oral Bacteria in Mediating Gemcitabine Resistance in Pancreatic Cancer |
| title_fullStr | Role of Oral Bacteria in Mediating Gemcitabine Resistance in Pancreatic Cancer |
| title_full_unstemmed | Role of Oral Bacteria in Mediating Gemcitabine Resistance in Pancreatic Cancer |
| title_short | Role of Oral Bacteria in Mediating Gemcitabine Resistance in Pancreatic Cancer |
| title_sort | role of oral bacteria in mediating gemcitabine resistance in pancreatic cancer |
| topic | pancreatic cancer gemcitabine cytidine deaminase HPLC drug resistance host microbial interactions |
| url | https://www.mdpi.com/2218-273X/15/7/1018 |
| work_keys_str_mv | AT gengxu roleoforalbacteriainmediatinggemcitabineresistanceinpancreaticcancer AT yalingjiang roleoforalbacteriainmediatinggemcitabineresistanceinpancreaticcancer AT chensun roleoforalbacteriainmediatinggemcitabineresistanceinpancreaticcancer AT berndwbrandt roleoforalbacteriainmediatinggemcitabineresistanceinpancreaticcancer AT kamrannazmi roleoforalbacteriainmediatinggemcitabineresistanceinpancreaticcancer AT lucamorelli roleoforalbacteriainmediatinggemcitabineresistanceinpancreaticcancer AT giulialencioni roleoforalbacteriainmediatinggemcitabineresistanceinpancreaticcancer AT elisagiovannetti roleoforalbacteriainmediatinggemcitabineresistanceinpancreaticcancer AT dongmeideng roleoforalbacteriainmediatinggemcitabineresistanceinpancreaticcancer |