Browsing by Subject "Verteporfin"

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    The effects of verteporfin on non-small cell lung cancer
    (2016-08) Ackerman, Todd R., Jr; Quilliam, Lawrence A.; Wells, Clark D.; Goebl, Mark G.
    Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers and is the leading cause of cancer death in the Unites States. Better treatments must be devised in order to improve the prognosis of this disease. Verteporfin, an FDA approved drug, has recently been reported to downregulate a potential core pathway of NSCLC, the Hippo pathway. The pathway consists of a kinase cascade to control the transcriptional coactivators YAP and TAZ. When these transcriptional coactivators lack phosphorylation of key residues, they are able to translocate into the nucleus and bind to the TEAD member of transcription factors. This augments transcription for genes responsible for proliferation, survival, and stem maintenance. In this study, we report that verteporfin limits proliferation and survival of NSCLC and may potentially be a viable treatment option. Inhibition of cell survival dose-dependently correlated with inhibition of YAP-TEAD transcription target CTGF. We also report the covalent homo-oligomerization of p62, a prominent protein involved with autophagy, with the introduction of verteporfin into NSCLC cells.
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    Sphingosine Kinase 1 Deficiency in Smooth Muscle Cells Protects against Hypoxia-Mediated Pulmonary Hypertension via YAP1 Signaling
    (MDPI, 2022-11-22) Chen, Jiwang; Lockett, Angelia; Zhao, Shuangping; Huang, Long Shuang; Wang, Yifan; Wu, Weiwen; Tang, Ming; Haider, Shahzaib; Velez Rendon, Daniela; Khan, Raheel; Liu, Bing; Felesena, Nicholas; Sysol, Justin R.; Valdez-Jasso, Daniela; Tang, Haiyan; Bai, Yang; Natarajan, Viswanathan; Machado, Roberto F.; Medicine, School of Medicine
    Sphingosine kinase 1 (SPHK1) and the sphingosine-1-phosphate (S1P) signaling pathway have been shown to play a role in pulmonary arterial hypertension (PAH). S1P is an important stimulus for pulmonary artery smooth muscle cell (PASMC) proliferation and pulmonary vascular remodeling. We aimed to examine the specific roles of SPHK1 in PASMCs during pulmonary hypertension (PH) progression. We generated smooth muscle cell-specific, Sphk1-deficient (Sphk1f/f TaglnCre+) mice and isolated Sphk1-deficient PASMCs from SPHK1 knockout mice. We demonstrated that Sphk1f/f TaglnCre+ mice are protected from hypoxia or hypoxia/Sugen-mediated PH, and pulmonary vascular remodeling and that Sphk1-deficient PASMCs are less proliferative compared with ones isolated from wild-type (WT) siblings. S1P or hypoxia activated yes-associated protein 1 (YAP1) signaling by enhancing its translocation to the nucleus, which was dependent on SPHK1 enzymatic activity. Further, verteporfin, a pharmacologic YAP1 inhibitor, attenuated the S1P-mediated proliferation of hPASMCs, hypoxia-mediated PH, and pulmonary vascular remodeling in mice and hypoxia/Sugen-mediated severe PH in rats. Smooth muscle cell-specific SPHK1 plays an essential role in PH via YAP1 signaling, and YAP1 inhibition may have therapeutic potential in treating PH.