20(S)-Ginsenoside Rh2 overcomes gemcitabine resistance in pancreatic cancer by inhibiting LAMC2-Modulated ABC transporters
Introduction: Gemcitabine (GEM) is the first-line drug for pancreatic ductal adenocarcinoma (PDAC), but drug resistance severely restricts its chemotherapeutic efficacy. Laminin subunit γ2 (LAMC2) plays a crucial role in extracellular matrix formation in the development of GEM-resistance. However, t...
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Elsevier
2025-07-01
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| author | Yulin Wu Juan Zhang Yuanyang Tian William Chi Shing Cho Hong-Xi Xu Zhi-Xiu Lin Yan-Fang Xian |
| author_facet | Yulin Wu Juan Zhang Yuanyang Tian William Chi Shing Cho Hong-Xi Xu Zhi-Xiu Lin Yan-Fang Xian |
| author_sort | Yulin Wu |
| collection | DOAJ |
| description | Introduction: Gemcitabine (GEM) is the first-line drug for pancreatic ductal adenocarcinoma (PDAC), but drug resistance severely restricts its chemotherapeutic efficacy. Laminin subunit γ2 (LAMC2) plays a crucial role in extracellular matrix formation in the development of GEM-resistance. However, the biological function of LAMC2 in GEM resistance and its molecular mechanisms are still unclear. 20(S)-Ginsenoside Rh2 (Rh2), one of the principal active components isolated from Ginseng Radix et Rhizoma, possesses strong anti-tumor effects. However, the effects of Rh2 on overcoming GEM resistance and its action mechanisms remain to be elucidated. Objectives: This study aimed to determine the efficacy of Rh2 on overcoming GEM resistance and to explore its underlying molecular mechanisms. Methods: Clinical study, Western blotting, publicly available databases and bioinformatic analyses were performed to investigate the protein expression of LAMC2 in the GEM-resistant PDAC patients and the acquired GEM-resistant PDAC cells. Then, the effects of Rh2 on overcoming the GEM resistance in PDAC were evaluated both in vitro and in vivo. Stable silencing or overexpression of LAMC2 in the GEM-resistant PDAC cells were established for validating the role of LAMC2 on Rh2 overcoming the GEM resistance in PDAC. Results: The protein expression of LAMC2 was markedly increased in the GEM-resistant PDAC patient biopsies compared to the sensitive cases. The protein expression of LAMC2 was significantly higher in the acquired GEM-resistant PDAC cells than that in their parental cells. Rh2 enhanced the chemosensitivity of GEM in the GEM-resistant PDAC cells, and inhibited the tumor growth of Miapaca-2-GR cell-bearing mice and Krastm4Tyj Trp53tm1Brn Tg (Pdx1-cre/Esr1*) #Dam/J (KPC) mice. Rh2 effectively reversed the GEM resistance in Miapaca-2-GR and Capan-2-GR cells by inhibiting LAMC2 expression through regulating the ubiquitin–proteasome pathway. Knockdown of LAMC2 enhanced the chemosensitivity of GEM and the effects of Rh2 on overcoming the GEM resistance in PDAC cells and the orthotopic PDAC mouse model. Conversely, LAMC2 overexpression aggravated the chemoresistance of GEM and abolished the effects of Rh2 on overcoming GEM resistance via modulating ATP-binding cassette (ABC) transporters leading to the active GEM efflux. Conclusions: LAMC2 plays an important role in the GEM resistance in PDAC, and Rh2 is a potential adjuvant for overcoming the chemoresistance of GEM in PDAC. |
| format | Article |
| id | doaj-art-a0ffd7d9431d4d32bd88cbee90878c68 |
| institution | DOAJ |
| issn | 2090-1232 |
| language | English |
| publishDate | 2025-07-01 |
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| spelling | doaj-art-a0ffd7d9431d4d32bd88cbee90878c682025-08-20T03:22:50ZengElsevierJournal of Advanced Research2090-12322025-07-017374376010.1016/j.jare.2024.09.00620(S)-Ginsenoside Rh2 overcomes gemcitabine resistance in pancreatic cancer by inhibiting LAMC2-Modulated ABC transportersYulin Wu0Juan Zhang1Yuanyang Tian2William Chi Shing Cho3Hong-Xi Xu4Zhi-Xiu Lin5Yan-Fang Xian6School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, ChinaSchool of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, ChinaSchool of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, ChinaDepartment of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong, China; Department of Pathology, Queen Elizabeth Hospital, Kowloon, Hong Kong, ChinaSchool of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, PR ChinaSchool of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China; Hong Kong Institute of Integrative Medicine, The Chinese University of Hong Kong, Hong Kong, China; The Chinese University of Hong Kong Chinese Medicine Specialty Clinic cum Clinical Teaching and Research Centre, School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; Corresponding authors at: School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, HK 999077, PR China.School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China; The Chinese University of Hong Kong Chinese Medicine Specialty Clinic cum Clinical Teaching and Research Centre, School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; Corresponding authors at: School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, HK 999077, PR China.Introduction: Gemcitabine (GEM) is the first-line drug for pancreatic ductal adenocarcinoma (PDAC), but drug resistance severely restricts its chemotherapeutic efficacy. Laminin subunit γ2 (LAMC2) plays a crucial role in extracellular matrix formation in the development of GEM-resistance. However, the biological function of LAMC2 in GEM resistance and its molecular mechanisms are still unclear. 20(S)-Ginsenoside Rh2 (Rh2), one of the principal active components isolated from Ginseng Radix et Rhizoma, possesses strong anti-tumor effects. However, the effects of Rh2 on overcoming GEM resistance and its action mechanisms remain to be elucidated. Objectives: This study aimed to determine the efficacy of Rh2 on overcoming GEM resistance and to explore its underlying molecular mechanisms. Methods: Clinical study, Western blotting, publicly available databases and bioinformatic analyses were performed to investigate the protein expression of LAMC2 in the GEM-resistant PDAC patients and the acquired GEM-resistant PDAC cells. Then, the effects of Rh2 on overcoming the GEM resistance in PDAC were evaluated both in vitro and in vivo. Stable silencing or overexpression of LAMC2 in the GEM-resistant PDAC cells were established for validating the role of LAMC2 on Rh2 overcoming the GEM resistance in PDAC. Results: The protein expression of LAMC2 was markedly increased in the GEM-resistant PDAC patient biopsies compared to the sensitive cases. The protein expression of LAMC2 was significantly higher in the acquired GEM-resistant PDAC cells than that in their parental cells. Rh2 enhanced the chemosensitivity of GEM in the GEM-resistant PDAC cells, and inhibited the tumor growth of Miapaca-2-GR cell-bearing mice and Krastm4Tyj Trp53tm1Brn Tg (Pdx1-cre/Esr1*) #Dam/J (KPC) mice. Rh2 effectively reversed the GEM resistance in Miapaca-2-GR and Capan-2-GR cells by inhibiting LAMC2 expression through regulating the ubiquitin–proteasome pathway. Knockdown of LAMC2 enhanced the chemosensitivity of GEM and the effects of Rh2 on overcoming the GEM resistance in PDAC cells and the orthotopic PDAC mouse model. Conversely, LAMC2 overexpression aggravated the chemoresistance of GEM and abolished the effects of Rh2 on overcoming GEM resistance via modulating ATP-binding cassette (ABC) transporters leading to the active GEM efflux. Conclusions: LAMC2 plays an important role in the GEM resistance in PDAC, and Rh2 is a potential adjuvant for overcoming the chemoresistance of GEM in PDAC.http://www.sciencedirect.com/science/article/pii/S209012322400390420(S)-Ginsenoside Rh2 (Rh2)Gemcitabine (GEM) resistancePancreatic ductal adenocarcinoma (PDAC)Laminin subunit γ2 (LAMC2) expressionATP-binding cassette (ABC) transporters |
| spellingShingle | Yulin Wu Juan Zhang Yuanyang Tian William Chi Shing Cho Hong-Xi Xu Zhi-Xiu Lin Yan-Fang Xian 20(S)-Ginsenoside Rh2 overcomes gemcitabine resistance in pancreatic cancer by inhibiting LAMC2-Modulated ABC transporters Journal of Advanced Research 20(S)-Ginsenoside Rh2 (Rh2) Gemcitabine (GEM) resistance Pancreatic ductal adenocarcinoma (PDAC) Laminin subunit γ2 (LAMC2) expression ATP-binding cassette (ABC) transporters |
| title | 20(S)-Ginsenoside Rh2 overcomes gemcitabine resistance in pancreatic cancer by inhibiting LAMC2-Modulated ABC transporters |
| title_full | 20(S)-Ginsenoside Rh2 overcomes gemcitabine resistance in pancreatic cancer by inhibiting LAMC2-Modulated ABC transporters |
| title_fullStr | 20(S)-Ginsenoside Rh2 overcomes gemcitabine resistance in pancreatic cancer by inhibiting LAMC2-Modulated ABC transporters |
| title_full_unstemmed | 20(S)-Ginsenoside Rh2 overcomes gemcitabine resistance in pancreatic cancer by inhibiting LAMC2-Modulated ABC transporters |
| title_short | 20(S)-Ginsenoside Rh2 overcomes gemcitabine resistance in pancreatic cancer by inhibiting LAMC2-Modulated ABC transporters |
| title_sort | 20 s ginsenoside rh2 overcomes gemcitabine resistance in pancreatic cancer by inhibiting lamc2 modulated abc transporters |
| topic | 20(S)-Ginsenoside Rh2 (Rh2) Gemcitabine (GEM) resistance Pancreatic ductal adenocarcinoma (PDAC) Laminin subunit γ2 (LAMC2) expression ATP-binding cassette (ABC) transporters |
| url | http://www.sciencedirect.com/science/article/pii/S2090123224003904 |
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