TY - JOUR
T1 - Dipyridamole Inhibits Lipogenic Gene Expression by Retaining SCAP-SREBP in the Endoplasmic Reticulum
AU - Esquejo, Ryan M.
AU - Roqueta-Rivera, Manuel
AU - Shao, Wei
AU - Phelan, Peter E.
AU - Seneviratne, Uthpala
AU - am Ende, Christopher W.
AU - Hershberger, Paul M.
AU - Machamer, Carolyn E.
AU - Espenshade, Peter J.
AU - Osborne, Timothy F.
N1 - Funding Information:
We are grateful to Dr. Linda Penn for introducing us to the dipyridamole project. We thank Drs. Michael S. Brown and Joseph L. Goldstein for providing us CHO-7 cells; Dr. Jared Rutter for pQCXIN-3xFLAG-SREBP plasmids; Dr. Fabienne Foufelle for the Insig2 antibody; Dr. Russell DeBose-Boyd for the Myc-S1P-KDEL plasmid; and Pfizer Inc for the clickable photoprobe PF-07079672. We are also grateful to our former student interns Rupert Faltlhauser and Mitchell Thomas for their dedication and technical assistance. We thank the Sanford Burnham Prebys Medical Discovery Institute Cell Imaging Core (Humberto Ibarra Avila). This research was supported by NIH, United States grants HL48044 (to T.F.O.) and HL077588 (to P.J.E.). Conceptualization, R.M.E. and T.F.O.; Methodology, R.M.E. M.R.-R. W.S. P.E.P. U.S. C.W.a.E. P.M.H. C.E.M. P.J.E. and T.F.O.; Investigation, R.M.E. M.R.-R. W.S. P.E.P. and U.S.; Resources, C.W.a.E. P.M.H. C.E.M. P.J.E. and T.F.O.; Writing – Original Draft, R.M.E. and T.F.O.; Writing – Review & Editing, R.M.E. M.R.-R. W.S. P.E.P. C.W.a.E. P.M.H. C.E.M. P.J.E. and T.F.O.; Supervision, R.M.E. P.J.E. and T.F.O.; Project Administration, R.M.E. and T.F.O.; Funding Acquisition, P.J.E. and T.F.O. During completion of these studies, R.M.E. U.S. and C.W.a.E. were employed by Pfizer Inc. and M.R.-R. was employed by Enanta Pharmaceuticals.
Funding Information:
We are grateful to Dr. Linda Penn for introducing us to the dipyridamole project. We thank Drs. Michael S. Brown and Joseph L. Goldstein for providing us CHO-7 cells; Dr. Jared Rutter for pQCXIN-3xFLAG-SREBP plasmids; Dr. Fabienne Foufelle for the Insig2 antibody; Dr. Russell DeBose-Boyd for the Myc-S1P-KDEL plasmid; and Pfizer Inc for the clickable photoprobe PF-07079672. We are also grateful to our former student interns Rupert Faltlhauser and Mitchell Thomas for their dedication and technical assistance. We thank the Sanford Burnham Prebys Medical Discovery Institute Cell Imaging Core (Humberto Ibarra Avila). This research was supported by NIH , United States grants HL48044 (to T.F.O.) and HL077588 (to P.J.E.).
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2021/2/18
Y1 - 2021/2/18
N2 - Sterol regulatory element-binding proteins (SREBPs) are master transcriptional regulators of the mevalonate pathway and lipid metabolism and represent an attractive therapeutic target for lipid metabolic disorders. SREBPs are maintained in the endoplasmic reticulum (ER) in a tripartite complex with SREBP cleavage-activating protein (SCAP) and insulin-induced gene protein (INSIG). When new lipid synthesis is required, the SCAP-SREBP complex dissociates from INSIG and undergoes ER-to-Golgi transport where the N-terminal transcription factor domain is released by proteolysis. The mature transcription factor translocates to the nucleus and stimulates expression of the SREBP gene program. Previous studies showed that dipyridamole, a clinically prescribed phosphodiesterase (PDE) inhibitor, potentiated statin-induced tumor growth inhibition. Dipyridamole limited nuclear accumulation of SREBP, but the mechanism was not well resolved. In this study, we show that dipyridamole selectively blocks ER-to-Golgi movement of the SCAP-SREBP complex and that this is independent of its PDE inhibitory activity.
AB - Sterol regulatory element-binding proteins (SREBPs) are master transcriptional regulators of the mevalonate pathway and lipid metabolism and represent an attractive therapeutic target for lipid metabolic disorders. SREBPs are maintained in the endoplasmic reticulum (ER) in a tripartite complex with SREBP cleavage-activating protein (SCAP) and insulin-induced gene protein (INSIG). When new lipid synthesis is required, the SCAP-SREBP complex dissociates from INSIG and undergoes ER-to-Golgi transport where the N-terminal transcription factor domain is released by proteolysis. The mature transcription factor translocates to the nucleus and stimulates expression of the SREBP gene program. Previous studies showed that dipyridamole, a clinically prescribed phosphodiesterase (PDE) inhibitor, potentiated statin-induced tumor growth inhibition. Dipyridamole limited nuclear accumulation of SREBP, but the mechanism was not well resolved. In this study, we show that dipyridamole selectively blocks ER-to-Golgi movement of the SCAP-SREBP complex and that this is independent of its PDE inhibitory activity.
KW - Insig
KW - SCAP inhibitor
KW - SREBP
KW - cancer
KW - cholesterol
KW - gene expression
KW - lipogenesis
KW - obesity
KW - repurposing dipyridamole
KW - triglycerides
UR - http://www.scopus.com/inward/record.url?scp=85097065624&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097065624&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2020.10.003
DO - 10.1016/j.chembiol.2020.10.003
M3 - Article
C2 - 33096051
AN - SCOPUS:85097065624
SN - 2451-9456
VL - 28
SP - 169-179.e7
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 2
ER -