Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade
Ursolic acid (UA), a pentacyclic triterpenoid extracted from various plants, inhibits cell growth, metastasis, and tumorigenesis in various cancers. Chemotherapy resistance and the side effects of paclitaxel (PTX), a traditional chemotherapy reagent, have limited the curative effect of PTX in esopha...
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2021-10-01
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| Series: | International Journal of Molecular Sciences |
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| author | Ruo Yu Meng Hua Jin Thi Van Nguyen Ok-Hee Chai Byung-Hyun Park Soo Mi Kim |
| author_facet | Ruo Yu Meng Hua Jin Thi Van Nguyen Ok-Hee Chai Byung-Hyun Park Soo Mi Kim |
| author_sort | Ruo Yu Meng |
| collection | DOAJ |
| description | Ursolic acid (UA), a pentacyclic triterpenoid extracted from various plants, inhibits cell growth, metastasis, and tumorigenesis in various cancers. Chemotherapy resistance and the side effects of paclitaxel (PTX), a traditional chemotherapy reagent, have limited the curative effect of PTX in esophageal cancer. In this study, we investigate whether UA promotes the anti-tumor effect of PTX and explore the underlying mechanism of their combined effect in esophageal squamous cell carcinoma (ESCC). Combination treatment with UA and PTX inhibited cell proliferation and cell growth more effectively than either treatment alone by inducing more significant apoptosis, as indicated by increased sub-G1 phase distribution and protein levels of cleaved-PARP and cleaved caspase-9. Similar to the cell growth suppressive effect, the combination of UA and PTX significantly inhibited cell migration by targeting uPA, MMP-9, and E-cadherin in ESCC cells. In addition, combination treatment with UA and PTX significantly activated p-GSK-3β and suppressed the activation of Akt and FOXM1 in ESCC cells. Those effects were enhanced by the Akt inhibitor LY2940002 and inverted by the Akt agonist SC79. In an in vivo evaluation of a murine xenograft model of esophageal cancer, combination treatment with UA and PTX suppressed tumor growth significantly better than UA or PTX treatment alone. Thus, UA effectively potentiates the anti-tumor efficacy of PTX by targeting the Akt/FOXM1 cascade since combination treatment shows significantly more anti-tumor potential than PTX alone both in vitro and in vivo. Combination treatment with UA and PTX could be a new strategy for curing esophageal cancer patients. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:02:03Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d28bd70cecc64f66bf6cb2ef10fc42352023-11-22T20:52:56ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122211148610.3390/ijms222111486Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling CascadeRuo Yu Meng0Hua Jin1Thi Van Nguyen2Ok-Hee Chai3Byung-Hyun Park4Soo Mi Kim5Department of Physiology, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, KoreaSchool of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, ChinaDepartment of Anatomy, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, KoreaDepartment of Anatomy, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, KoreaDepartment of Biochemistry, Jeonbuk National University Medical School, Jeonju 54907, KoreaDepartment of Physiology, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju 54907, KoreaUrsolic acid (UA), a pentacyclic triterpenoid extracted from various plants, inhibits cell growth, metastasis, and tumorigenesis in various cancers. Chemotherapy resistance and the side effects of paclitaxel (PTX), a traditional chemotherapy reagent, have limited the curative effect of PTX in esophageal cancer. In this study, we investigate whether UA promotes the anti-tumor effect of PTX and explore the underlying mechanism of their combined effect in esophageal squamous cell carcinoma (ESCC). Combination treatment with UA and PTX inhibited cell proliferation and cell growth more effectively than either treatment alone by inducing more significant apoptosis, as indicated by increased sub-G1 phase distribution and protein levels of cleaved-PARP and cleaved caspase-9. Similar to the cell growth suppressive effect, the combination of UA and PTX significantly inhibited cell migration by targeting uPA, MMP-9, and E-cadherin in ESCC cells. In addition, combination treatment with UA and PTX significantly activated p-GSK-3β and suppressed the activation of Akt and FOXM1 in ESCC cells. Those effects were enhanced by the Akt inhibitor LY2940002 and inverted by the Akt agonist SC79. In an in vivo evaluation of a murine xenograft model of esophageal cancer, combination treatment with UA and PTX suppressed tumor growth significantly better than UA or PTX treatment alone. Thus, UA effectively potentiates the anti-tumor efficacy of PTX by targeting the Akt/FOXM1 cascade since combination treatment shows significantly more anti-tumor potential than PTX alone both in vitro and in vivo. Combination treatment with UA and PTX could be a new strategy for curing esophageal cancer patients.https://www.mdpi.com/1422-0067/22/21/11486ursolic acidesophageal squamous cell carcinomaapoptosisFOXM1Akt |
| spellingShingle | Ruo Yu Meng Hua Jin Thi Van Nguyen Ok-Hee Chai Byung-Hyun Park Soo Mi Kim Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade International Journal of Molecular Sciences ursolic acid esophageal squamous cell carcinoma apoptosis FOXM1 Akt |
| title | Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade |
| title_full | Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade |
| title_fullStr | Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade |
| title_full_unstemmed | Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade |
| title_short | Ursolic Acid Accelerates Paclitaxel-Induced Cell Death in Esophageal Cancer Cells by Suppressing Akt/FOXM1 Signaling Cascade |
| title_sort | ursolic acid accelerates paclitaxel induced cell death in esophageal cancer cells by suppressing akt foxm1 signaling cascade |
| topic | ursolic acid esophageal squamous cell carcinoma apoptosis FOXM1 Akt |
| url | https://www.mdpi.com/1422-0067/22/21/11486 |
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