Inhibition of phosphodiesterase 4D suppresses mTORC1 signaling and pancreatic cancer growth
The mammalian target of rapamycin complex 1 (mTORC1) senses multiple upstream stimuli to orchestrate anabolic and catabolic events that regulate cell growth and metabolism. Hyperactivation of mTORC1 signaling is observed in multiple human diseases; thus, pathways that suppress mTORC1 signaling may h...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-07-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.158098 |
| _version_ | 1797634316980715520 |
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| author | Mi-Hyeon Jeong Greg Urquhart Cheryl Lewis Zhikai Chi Jenna L. Jewell |
| author_facet | Mi-Hyeon Jeong Greg Urquhart Cheryl Lewis Zhikai Chi Jenna L. Jewell |
| author_sort | Mi-Hyeon Jeong |
| collection | DOAJ |
| description | The mammalian target of rapamycin complex 1 (mTORC1) senses multiple upstream stimuli to orchestrate anabolic and catabolic events that regulate cell growth and metabolism. Hyperactivation of mTORC1 signaling is observed in multiple human diseases; thus, pathways that suppress mTORC1 signaling may help to identify new therapeutic targets. Here, we report that phosphodiesterase 4D (PDE4D) promotes pancreatic cancer tumor growth by increasing mTORC1 signaling. GPCRs paired to Gαs proteins activate adenylyl cyclase, which in turn elevates levels of 3′,5′-cyclic adenosine monophosphate (cAMP), whereas PDEs catalyze the hydrolysis of cAMP to 5′-AMP. PDE4D forms a complex with mTORC1 and is required for mTORC1 lysosomal localization and activation. Inhibition of PDE4D and the elevation of cAMP levels block mTORC1 signaling via Raptor phosphorylation. Moreover, pancreatic cancer exhibits an upregulation of PDE4D expression, and high PDE4D levels predict the poor overall survival of patients with pancreatic cancer. Importantly, FDA-approved PDE4 inhibitors repress pancreatic cancer cell tumor growth in vivo by suppressing mTORC1 signaling. Our results identify PDE4D as an important activator of mTORC1 and suggest that targeting PDE4 with FDA-approved inhibitors may be beneficial for the treatment of human diseases with hyperactivated mTORC1 signaling. |
| first_indexed | 2024-03-11T12:05:56Z |
| format | Article |
| id | doaj.art-b0e8b281061e4634ab98ed5a5893bba5 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:05:56Z |
| publishDate | 2023-07-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-b0e8b281061e4634ab98ed5a5893bba52023-11-07T16:25:50ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-07-01813Inhibition of phosphodiesterase 4D suppresses mTORC1 signaling and pancreatic cancer growthMi-Hyeon JeongGreg UrquhartCheryl LewisZhikai ChiJenna L. JewellThe mammalian target of rapamycin complex 1 (mTORC1) senses multiple upstream stimuli to orchestrate anabolic and catabolic events that regulate cell growth and metabolism. Hyperactivation of mTORC1 signaling is observed in multiple human diseases; thus, pathways that suppress mTORC1 signaling may help to identify new therapeutic targets. Here, we report that phosphodiesterase 4D (PDE4D) promotes pancreatic cancer tumor growth by increasing mTORC1 signaling. GPCRs paired to Gαs proteins activate adenylyl cyclase, which in turn elevates levels of 3′,5′-cyclic adenosine monophosphate (cAMP), whereas PDEs catalyze the hydrolysis of cAMP to 5′-AMP. PDE4D forms a complex with mTORC1 and is required for mTORC1 lysosomal localization and activation. Inhibition of PDE4D and the elevation of cAMP levels block mTORC1 signaling via Raptor phosphorylation. Moreover, pancreatic cancer exhibits an upregulation of PDE4D expression, and high PDE4D levels predict the poor overall survival of patients with pancreatic cancer. Importantly, FDA-approved PDE4 inhibitors repress pancreatic cancer cell tumor growth in vivo by suppressing mTORC1 signaling. Our results identify PDE4D as an important activator of mTORC1 and suggest that targeting PDE4 with FDA-approved inhibitors may be beneficial for the treatment of human diseases with hyperactivated mTORC1 signaling.https://doi.org/10.1172/jci.insight.158098Cell biology |
| spellingShingle | Mi-Hyeon Jeong Greg Urquhart Cheryl Lewis Zhikai Chi Jenna L. Jewell Inhibition of phosphodiesterase 4D suppresses mTORC1 signaling and pancreatic cancer growth JCI Insight Cell biology |
| title | Inhibition of phosphodiesterase 4D suppresses mTORC1 signaling and pancreatic cancer growth |
| title_full | Inhibition of phosphodiesterase 4D suppresses mTORC1 signaling and pancreatic cancer growth |
| title_fullStr | Inhibition of phosphodiesterase 4D suppresses mTORC1 signaling and pancreatic cancer growth |
| title_full_unstemmed | Inhibition of phosphodiesterase 4D suppresses mTORC1 signaling and pancreatic cancer growth |
| title_short | Inhibition of phosphodiesterase 4D suppresses mTORC1 signaling and pancreatic cancer growth |
| title_sort | inhibition of phosphodiesterase 4d suppresses mtorc1 signaling and pancreatic cancer growth |
| topic | Cell biology |
| url | https://doi.org/10.1172/jci.insight.158098 |
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