Difluoromethylornithine Induces Apoptosis through Regulation of AP-1 Signaling via JNK Phosphorylation in Epithelial Ovarian Cancer
Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), has promising activity against various cancers and a tolerable safety profile for long-term use as a chemopreventive agent. However, the anti-tumor effects of DFMO in ovarian cancer cells have not been entire...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-09-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/19/10255 |
| _version_ | 1797516378939326464 |
|---|---|
| author | Woo Yeon Hwang Wook Ha Park Dong Hoon Suh Kidong Kim Yong Beom Kim Jae Hong No |
| author_facet | Woo Yeon Hwang Wook Ha Park Dong Hoon Suh Kidong Kim Yong Beom Kim Jae Hong No |
| author_sort | Woo Yeon Hwang |
| collection | DOAJ |
| description | Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), has promising activity against various cancers and a tolerable safety profile for long-term use as a chemopreventive agent. However, the anti-tumor effects of DFMO in ovarian cancer cells have not been entirely understood. Our study aimed to identify the effects and mechanism of DFMO in epithelial ovarian cancer cells using SKOV-3 cells. Treatment with DFMO resulted in a significantly reduced cell viability in a time- and dose-dependent manner. DFMO treatment inhibited the activity and downregulated the expression of ODC in ovarian cancer cells. The reduction in cell viability was reversed using polyamines, suggesting that polyamine depletion plays an important role in the anti-tumor activity of DFMO. Additionally, significant changes in Bcl-2, Bcl-xL, Bax protein levels, activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase were observed, indicating the apoptotic effects of DFMO. We also found that the effect of DFMO was mediated by AP-1 through the activation of upstream JNK via phosphorylation. Moreover, DFMO enhanced the effect of cisplatin, thus showing a possibility of a synergistic effect in treatment. In conclusion, treatment with DFMO alone, or in combination with cisplatin, could be a promising treatment for ovarian cancer. |
| first_indexed | 2024-03-10T07:01:14Z |
| format | Article |
| id | doaj.art-f2144808744a433e8b53f7fdcf1f6e82 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T07:01:14Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f2144808744a433e8b53f7fdcf1f6e822023-11-22T16:06:48ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-09-0122191025510.3390/ijms221910255Difluoromethylornithine Induces Apoptosis through Regulation of AP-1 Signaling via JNK Phosphorylation in Epithelial Ovarian CancerWoo Yeon Hwang0Wook Ha Park1Dong Hoon Suh2Kidong Kim3Yong Beom Kim4Jae Hong No5Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam 13620, KoreaDepartment of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam 13620, KoreaDepartment of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam 13620, KoreaDepartment of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam 13620, KoreaDepartment of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam 13620, KoreaDepartment of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam 13620, KoreaDifluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC), has promising activity against various cancers and a tolerable safety profile for long-term use as a chemopreventive agent. However, the anti-tumor effects of DFMO in ovarian cancer cells have not been entirely understood. Our study aimed to identify the effects and mechanism of DFMO in epithelial ovarian cancer cells using SKOV-3 cells. Treatment with DFMO resulted in a significantly reduced cell viability in a time- and dose-dependent manner. DFMO treatment inhibited the activity and downregulated the expression of ODC in ovarian cancer cells. The reduction in cell viability was reversed using polyamines, suggesting that polyamine depletion plays an important role in the anti-tumor activity of DFMO. Additionally, significant changes in Bcl-2, Bcl-xL, Bax protein levels, activation of caspase-3, and cleavage of poly (ADP-ribose) polymerase were observed, indicating the apoptotic effects of DFMO. We also found that the effect of DFMO was mediated by AP-1 through the activation of upstream JNK via phosphorylation. Moreover, DFMO enhanced the effect of cisplatin, thus showing a possibility of a synergistic effect in treatment. In conclusion, treatment with DFMO alone, or in combination with cisplatin, could be a promising treatment for ovarian cancer.https://www.mdpi.com/1422-0067/22/19/10255AP-1apoptosisDFMOJNKovarian cancerpolyamines |
| spellingShingle | Woo Yeon Hwang Wook Ha Park Dong Hoon Suh Kidong Kim Yong Beom Kim Jae Hong No Difluoromethylornithine Induces Apoptosis through Regulation of AP-1 Signaling via JNK Phosphorylation in Epithelial Ovarian Cancer International Journal of Molecular Sciences AP-1 apoptosis DFMO JNK ovarian cancer polyamines |
| title | Difluoromethylornithine Induces Apoptosis through Regulation of AP-1 Signaling via JNK Phosphorylation in Epithelial Ovarian Cancer |
| title_full | Difluoromethylornithine Induces Apoptosis through Regulation of AP-1 Signaling via JNK Phosphorylation in Epithelial Ovarian Cancer |
| title_fullStr | Difluoromethylornithine Induces Apoptosis through Regulation of AP-1 Signaling via JNK Phosphorylation in Epithelial Ovarian Cancer |
| title_full_unstemmed | Difluoromethylornithine Induces Apoptosis through Regulation of AP-1 Signaling via JNK Phosphorylation in Epithelial Ovarian Cancer |
| title_short | Difluoromethylornithine Induces Apoptosis through Regulation of AP-1 Signaling via JNK Phosphorylation in Epithelial Ovarian Cancer |
| title_sort | difluoromethylornithine induces apoptosis through regulation of ap 1 signaling via jnk phosphorylation in epithelial ovarian cancer |
| topic | AP-1 apoptosis DFMO JNK ovarian cancer polyamines |
| url | https://www.mdpi.com/1422-0067/22/19/10255 |
| work_keys_str_mv | AT wooyeonhwang difluoromethylornithineinducesapoptosisthroughregulationofap1signalingviajnkphosphorylationinepithelialovariancancer AT wookhapark difluoromethylornithineinducesapoptosisthroughregulationofap1signalingviajnkphosphorylationinepithelialovariancancer AT donghoonsuh difluoromethylornithineinducesapoptosisthroughregulationofap1signalingviajnkphosphorylationinepithelialovariancancer AT kidongkim difluoromethylornithineinducesapoptosisthroughregulationofap1signalingviajnkphosphorylationinepithelialovariancancer AT yongbeomkim difluoromethylornithineinducesapoptosisthroughregulationofap1signalingviajnkphosphorylationinepithelialovariancancer AT jaehongno difluoromethylornithineinducesapoptosisthroughregulationofap1signalingviajnkphosphorylationinepithelialovariancancer |