Phosphodiesterase 10A: a novel target for selective inhibition of colon tumor cell growth and β-catenin-dependent TCF transcriptional activity.
The cyclic nucleotide phosphodiesterase 10A (PDE10) has been mostly studied as a therapeutic target for certain psychiatric and neurological conditions, although a potential role in tumorigenesis has not been reported. Here we show that PDE10 is elevated in human colon tumor cell lines compared with normal colonocytes, as well as in colon tumors from human clinical specimens and intestinal tumors from Apc(Min/+) mice compared with normal intestinal mucosa, respectively. An isozyme and tumor-selective role of PDE10 were evident by the ability of small-molecule inhibitors and small interfering RNA knockdown to suppress colon tumor cell growth with reduced sensitivity of normal colonocytes. Stable knockdown of PDE10 by short hairpin RNA also inhibits colony formation and increases doubling time of colon tumor cells. PDE10 inhibition selectively activates cGMP/cGMP-dependent protein kinase signaling to suppress β-catenin levels and T-cell factor (TCF) transcriptional activity in colon tumor cells. Conversely, ectopic expression of PDE10 in normal and precancerous colonocytes increases proliferation and activates TCF transcriptional activity. These observations suggest a novel role of PDE10 in colon tumorigenesis and that inhibitors may be useful for the treatment or prevention of colorectal cancer.
Department of Biochemistry and Molecular Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA.
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N
Li
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
K
K
Lee
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
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Y
Xi
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
B
B
Zhu
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
B D
BD
Gary
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
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Ramírez-Alcántara
Department of Pharmacology and Toxicology, The University of Alabama at Birmingham, Birmingham, AL, USA.
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E
Gurpinar
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
J C
JC
Canzoneri
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
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A
Fajardo
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
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Sigler
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
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JT
Piazza
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
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X
Chen
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
J
J
Andrews
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
M
M
Thomas
Drug Discovery Division, Southern Research Institute, Birmingham, AL, USA.
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W
Lu
Drug Discovery Division, Southern Research Institute, Birmingham, AL, USA.
Y
Y
Li
School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA.
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Laan
INCELL Corporation LLC, San Antonio, TX, USA.
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Moyer
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
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S
Russo
Department of Chemistry, University of South Alabama, Mobile, AL, USA.
B T
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Eberhardt
Department of Chemistry, University of South Alabama, Mobile, AL, USA.
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L
Yet
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
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AB
Keeton
Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA.
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Grizzle
Department of Oncologic Sciences and Pharmacology, Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
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Piazza
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051820:TCF Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
C495270:CTNNB1 protein, human; D010726:Phosphodiesterase Inhibitors; D034741:RNA, Small Interfering; D051820:TCF Transcription Factors; D051176:beta Catenin; C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases