PDE4D targeting enhances anti-tumor effects of sorafenib in clear cell renal cell carcinoma and attenuates MAPK/ERK signaling in a CRAF-dependent manner
Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer and effective treatment regimens are yet to be established. Tyrosine kinase inhibitors (TKI) have widely been used as ccRCC therapeutics, but their efficacy is limited due to accompanying resistance mechanisms. Previous...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-05-01
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| Series: | Translational Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523322000390 |
| _version_ | 1818644861787570176 |
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| author | Minghua Cao Karol Nawalaniec Amrendra K. Ajay Yueming Luo Romana Moench Yanfei Jin Sheng Xiao Li-Li Hsiao Ana Maria Waaga-Gasser |
| author_facet | Minghua Cao Karol Nawalaniec Amrendra K. Ajay Yueming Luo Romana Moench Yanfei Jin Sheng Xiao Li-Li Hsiao Ana Maria Waaga-Gasser |
| author_sort | Minghua Cao |
| collection | DOAJ |
| description | Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer and effective treatment regimens are yet to be established. Tyrosine kinase inhibitors (TKI) have widely been used as ccRCC therapeutics, but their efficacy is limited due to accompanying resistance mechanisms. Previous studies have provided substantial evidence for crosstalk between cAMP and the MAPK/ERK signaling pathway. Low levels of intracellular cAMP have been found in several human malignancies and some data suggest that elevation of cAMP expression can be achieved by phosphodiesterase 4 (PDE4) inhibition, resulting in cell growth arrest and/or cell death. The effects of crosstalk between cAMP and the MAPK/ERK pathway on the development progression in ccRCR, however, remain to be fully understood. In this study, we sought to explore the involvement of PDE4 in ccRCC and to assess its potential as a target for therapeutic intervention. We demonstrated that PDE4D is the predominant subtype of PDE4 expressed in healthy and cancerous renal cell lines, particularly in metastatic Caki-1 cells. We generated a CRISPR/Cas9-mediated PDE4D-KO Caki-1 cell model and showed that PDE4D depletion reduced cell proliferation and recovered cAMP expression in these cells. PDE4D-KO and/or PDE4 inhibition with the FDA approved PDE4 inhibitor, roflumilast, also attenuated MAPK/ERK signaling in a CRAF-dependent manner. Most interestingly, we showed that PDE4D-KO enhanced the effectiveness of the TKI, sorafenib, to stunt cell survival. In conclusion, we provide preliminary evidence of PDE4 involvement in ccRCC and suggest a rationale for dual tyrosine kinase/PDE4D targeting in patients with CRAF-dependent MAPK activation. |
| first_indexed | 2024-12-17T00:21:35Z |
| format | Article |
| id | doaj.art-5770d635e6b24c4bbdcaa37cd2d588f4 |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-12-17T00:21:35Z |
| publishDate | 2022-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-5770d635e6b24c4bbdcaa37cd2d588f42022-12-21T22:10:33ZengElsevierTranslational Oncology1936-52332022-05-0119101377PDE4D targeting enhances anti-tumor effects of sorafenib in clear cell renal cell carcinoma and attenuates MAPK/ERK signaling in a CRAF-dependent mannerMinghua Cao0Karol Nawalaniec1Amrendra K. Ajay2Yueming Luo3Romana Moench4Yanfei Jin5Sheng Xiao6Li-Li Hsiao7Ana Maria Waaga-Gasser8Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, BLI Rm 449, Boston, MA 02115, USA; The Sixth People's Hospital of Nantong, Affiliated Nantong Hospital of Shanghai University, Nantong, Jiangsu 226011, ChinaDepartment of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, BLI Rm 449, Boston, MA 02115, USADepartment of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, BLI Rm 449, Boston, MA 02115, USADepartment of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, BLI Rm 449, Boston, MA 02115, USADepartment of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, BLI Rm 449, Boston, MA 02115, USAThe Sixth People's Hospital of Nantong, Affiliated Nantong Hospital of Shanghai University, Nantong, Jiangsu 226011, ChinaDepartment of Pathology, Cytogenetics Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USADepartment of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, BLI Rm 449, Boston, MA 02115, USA; Corresponding authors.Department of Medicine, Renal Division, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, BLI Rm 449, Boston, MA 02115, USA; Corresponding authors.Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer and effective treatment regimens are yet to be established. Tyrosine kinase inhibitors (TKI) have widely been used as ccRCC therapeutics, but their efficacy is limited due to accompanying resistance mechanisms. Previous studies have provided substantial evidence for crosstalk between cAMP and the MAPK/ERK signaling pathway. Low levels of intracellular cAMP have been found in several human malignancies and some data suggest that elevation of cAMP expression can be achieved by phosphodiesterase 4 (PDE4) inhibition, resulting in cell growth arrest and/or cell death. The effects of crosstalk between cAMP and the MAPK/ERK pathway on the development progression in ccRCR, however, remain to be fully understood. In this study, we sought to explore the involvement of PDE4 in ccRCC and to assess its potential as a target for therapeutic intervention. We demonstrated that PDE4D is the predominant subtype of PDE4 expressed in healthy and cancerous renal cell lines, particularly in metastatic Caki-1 cells. We generated a CRISPR/Cas9-mediated PDE4D-KO Caki-1 cell model and showed that PDE4D depletion reduced cell proliferation and recovered cAMP expression in these cells. PDE4D-KO and/or PDE4 inhibition with the FDA approved PDE4 inhibitor, roflumilast, also attenuated MAPK/ERK signaling in a CRAF-dependent manner. Most interestingly, we showed that PDE4D-KO enhanced the effectiveness of the TKI, sorafenib, to stunt cell survival. In conclusion, we provide preliminary evidence of PDE4 involvement in ccRCC and suggest a rationale for dual tyrosine kinase/PDE4D targeting in patients with CRAF-dependent MAPK activation.http://www.sciencedirect.com/science/article/pii/S1936523322000390Phosphodiesterase 4DcAMPRenal cell carcinomaTyrosine kinase inhibitorMAPK/ERK pathwayCRAF |
| spellingShingle | Minghua Cao Karol Nawalaniec Amrendra K. Ajay Yueming Luo Romana Moench Yanfei Jin Sheng Xiao Li-Li Hsiao Ana Maria Waaga-Gasser PDE4D targeting enhances anti-tumor effects of sorafenib in clear cell renal cell carcinoma and attenuates MAPK/ERK signaling in a CRAF-dependent manner Translational Oncology Phosphodiesterase 4D cAMP Renal cell carcinoma Tyrosine kinase inhibitor MAPK/ERK pathway CRAF |
| title | PDE4D targeting enhances anti-tumor effects of sorafenib in clear cell renal cell carcinoma and attenuates MAPK/ERK signaling in a CRAF-dependent manner |
| title_full | PDE4D targeting enhances anti-tumor effects of sorafenib in clear cell renal cell carcinoma and attenuates MAPK/ERK signaling in a CRAF-dependent manner |
| title_fullStr | PDE4D targeting enhances anti-tumor effects of sorafenib in clear cell renal cell carcinoma and attenuates MAPK/ERK signaling in a CRAF-dependent manner |
| title_full_unstemmed | PDE4D targeting enhances anti-tumor effects of sorafenib in clear cell renal cell carcinoma and attenuates MAPK/ERK signaling in a CRAF-dependent manner |
| title_short | PDE4D targeting enhances anti-tumor effects of sorafenib in clear cell renal cell carcinoma and attenuates MAPK/ERK signaling in a CRAF-dependent manner |
| title_sort | pde4d targeting enhances anti tumor effects of sorafenib in clear cell renal cell carcinoma and attenuates mapk erk signaling in a craf dependent manner |
| topic | Phosphodiesterase 4D cAMP Renal cell carcinoma Tyrosine kinase inhibitor MAPK/ERK pathway CRAF |
| url | http://www.sciencedirect.com/science/article/pii/S1936523322000390 |
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