Rhus coriaria (Sumac) induces autophagic cell death and inhibits mTOR, p38MAPK and STAT3 pathways in 5fluorouracil-resistant colorectal cancer cells
IntroductionColorectal cancer is a leading cause of cancer related-death worldwide, and resistance to 5-fluorouracil (5FU, a key component of chemotherapy regimens, is a major clinical concern. We have previously elucidated the effects of Rhus coriaria ethanolic extract (RCE) in triple-negative brea...
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Frontiers Media S.A.
2025-03-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1542204/full |
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| author | Zohra Nausheen Nizami Mazoun Al Azzani Samah Khaldi Adil Farooq Wali Rym Magramane Shamaa Abdul Samad Ali H. Eid Kholoud Arafat Yusra Al Dhaheri Samir Attoub Rabah Iratni |
| author_facet | Zohra Nausheen Nizami Mazoun Al Azzani Samah Khaldi Adil Farooq Wali Rym Magramane Shamaa Abdul Samad Ali H. Eid Kholoud Arafat Yusra Al Dhaheri Samir Attoub Rabah Iratni |
| author_sort | Zohra Nausheen Nizami |
| collection | DOAJ |
| description | IntroductionColorectal cancer is a leading cause of cancer related-death worldwide, and resistance to 5-fluorouracil (5FU, a key component of chemotherapy regimens, is a major clinical concern. We have previously elucidated the effects of Rhus coriaria ethanolic extract (RCE) in triple-negative breast cancer, CRC, and pancreatic cancer cells. Here, we explored the anticancer effects of RCE in parental (HCT-116-WT) and 5FU-resistant HCT-116 (HCT-116-5FU-R) CRC cells.MethodsMTT assay was used to assess cell viability. Muse analyzer was used to assess cell viability, cell cycle distribution, and apoptosis. Additionally, colony formation and growth assays and western blots were performed. In vivo effects of RCE were assessed by an in ovo chick embryo tumor growth assay.ResultsWe found that RCE inhibited the viability and colony formation and growth capacities of HCT-116-WT and HCT-116-5FU-R cells. The antiproliferative effects were attributed to DNA damage-mediated impairment of cell cycle at S phase, and induction of Beclin-1-independent autophagy in both cell lines. Mechanistically, inhibition of the mTOR, STAT3 and p38 MAPK pathways was implicated in the latter. Additionally, RCE induced caspase-7-independent apoptosis in HCT-116-WT cells. However, HCT-116-5FU-R cells were resistant to apoptosis through upregulation of survivin, and downregulation of Bax. Using autophagy and proteasome inhibitors, we clarified that autophagy and the proteasome pathway contributed to RCE-mediated cell death in HCT-116-WT and HCT-116-5FU-R cells. Lastly, we confirmed RCE inhibited the growth of both HCT-116-WT and HCT-116-5FU-R xenografts in a chick embryo model.DiscussionCollectively, our findings highlight that RCE is a source of phytochemicals that can be used as anticancer agents for 5FU-resistant CRC. |
| format | Article |
| id | doaj-art-87f242c8cd054fce84fdc7216b5de2b6 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-03-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-87f242c8cd054fce84fdc7216b5de2b62025-08-20T03:42:38ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-03-011610.3389/fphar.2025.15422041542204Rhus coriaria (Sumac) induces autophagic cell death and inhibits mTOR, p38MAPK and STAT3 pathways in 5fluorouracil-resistant colorectal cancer cellsZohra Nausheen Nizami0Mazoun Al Azzani1Samah Khaldi2Adil Farooq Wali3Rym Magramane4Shamaa Abdul Samad5Ali H. Eid6Kholoud Arafat7Yusra Al Dhaheri8Samir Attoub9Rabah Iratni10Department of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab EmiratesDepartment of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab EmiratesDepartment of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab EmiratesDepartment of Pharmaceutical Chemistry, RAK College of Pharmacy, RAK Medical and Health Sciences University, Ras Al Khaimah, United Arab EmiratesDepartment of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab EmiratesDepartment of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab EmiratesDepartment of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, QatarDepartment of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab EmiratesDepartment of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab EmiratesDepartment of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab EmiratesDepartment of Biology, College of Science, United Arab Emirates University, Al-Ain, United Arab EmiratesIntroductionColorectal cancer is a leading cause of cancer related-death worldwide, and resistance to 5-fluorouracil (5FU, a key component of chemotherapy regimens, is a major clinical concern. We have previously elucidated the effects of Rhus coriaria ethanolic extract (RCE) in triple-negative breast cancer, CRC, and pancreatic cancer cells. Here, we explored the anticancer effects of RCE in parental (HCT-116-WT) and 5FU-resistant HCT-116 (HCT-116-5FU-R) CRC cells.MethodsMTT assay was used to assess cell viability. Muse analyzer was used to assess cell viability, cell cycle distribution, and apoptosis. Additionally, colony formation and growth assays and western blots were performed. In vivo effects of RCE were assessed by an in ovo chick embryo tumor growth assay.ResultsWe found that RCE inhibited the viability and colony formation and growth capacities of HCT-116-WT and HCT-116-5FU-R cells. The antiproliferative effects were attributed to DNA damage-mediated impairment of cell cycle at S phase, and induction of Beclin-1-independent autophagy in both cell lines. Mechanistically, inhibition of the mTOR, STAT3 and p38 MAPK pathways was implicated in the latter. Additionally, RCE induced caspase-7-independent apoptosis in HCT-116-WT cells. However, HCT-116-5FU-R cells were resistant to apoptosis through upregulation of survivin, and downregulation of Bax. Using autophagy and proteasome inhibitors, we clarified that autophagy and the proteasome pathway contributed to RCE-mediated cell death in HCT-116-WT and HCT-116-5FU-R cells. Lastly, we confirmed RCE inhibited the growth of both HCT-116-WT and HCT-116-5FU-R xenografts in a chick embryo model.DiscussionCollectively, our findings highlight that RCE is a source of phytochemicals that can be used as anticancer agents for 5FU-resistant CRC.https://www.frontiersin.org/articles/10.3389/fphar.2025.1542204/full5-fluorouracilchemoresistancecolorectal cancerapoptosisautophagySurvivin |
| spellingShingle | Zohra Nausheen Nizami Mazoun Al Azzani Samah Khaldi Adil Farooq Wali Rym Magramane Shamaa Abdul Samad Ali H. Eid Kholoud Arafat Yusra Al Dhaheri Samir Attoub Rabah Iratni Rhus coriaria (Sumac) induces autophagic cell death and inhibits mTOR, p38MAPK and STAT3 pathways in 5fluorouracil-resistant colorectal cancer cells Frontiers in Pharmacology 5-fluorouracil chemoresistance colorectal cancer apoptosis autophagy Survivin |
| title | Rhus coriaria (Sumac) induces autophagic cell death and inhibits mTOR, p38MAPK and STAT3 pathways in 5fluorouracil-resistant colorectal cancer cells |
| title_full | Rhus coriaria (Sumac) induces autophagic cell death and inhibits mTOR, p38MAPK and STAT3 pathways in 5fluorouracil-resistant colorectal cancer cells |
| title_fullStr | Rhus coriaria (Sumac) induces autophagic cell death and inhibits mTOR, p38MAPK and STAT3 pathways in 5fluorouracil-resistant colorectal cancer cells |
| title_full_unstemmed | Rhus coriaria (Sumac) induces autophagic cell death and inhibits mTOR, p38MAPK and STAT3 pathways in 5fluorouracil-resistant colorectal cancer cells |
| title_short | Rhus coriaria (Sumac) induces autophagic cell death and inhibits mTOR, p38MAPK and STAT3 pathways in 5fluorouracil-resistant colorectal cancer cells |
| title_sort | rhus coriaria sumac induces autophagic cell death and inhibits mtor p38mapk and stat3 pathways in 5fluorouracil resistant colorectal cancer cells |
| topic | 5-fluorouracil chemoresistance colorectal cancer apoptosis autophagy Survivin |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1542204/full |
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