Ribosome-inactivating proteins isolated from dietary bitter melon induce apoptosis and inhibit histone deacetylase-1 selectively in premalignant and malignant prostate cancer cells.
Epidemiologic evidence suggests that a diet rich in fruits and vegetables is associated with a reduced risk of prostate cancer (PCa) development. Although several dietary compounds have been tested in preclinical PCa prevention models, no agents have been identified that either prevent the progression of premalignant lesions or treat advanced disease. Momordica charantia, known as bitter melon in English, is a plant that grows in tropical areas worldwide and is both eaten as a vegetable and used for medicinal purposes. We have isolated a protein, designated as MCP30, from bitter melon seeds. The purified fraction was verified by SDS-PAGE and mass spectrometry to contain only 2 highly related single chain Type I ribosome-inactivating proteins (RIPs), alpha-momorcharin and beta-momorcharin. MCP30 induces apoptosis in PIN and PCa cell lines in vitro and suppresses PC-3 growth in vivo with no effect on normal prostate cells. Mechanistically, MCP30 inhibits histone deacetylase-1 (HDAC-1) activity and promotes histone-3 and -4 protein acetylation. Treatment with MCP30 induces PTEN expression in a prostatic intraepithelial neoplasia (PIN) and PCa cell lines resulting in inhibition of Akt phosphorylation. In addition, MCP30 inhibits Wnt signaling activity through reduction of nuclear accumulation of beta-catenin and decreased levels of c-Myc and Cyclin-D1. Our data indicate that MCP30 selectively induces PIN and PCa apoptosis and inhibits HDAC-1 activity. These results suggest that Type I RIPs derived from plants are HDAC inhibitors that can be utilized in the prevention and treatment of prostate cancer.
Xiong
Su Dao
SD
Institute of Hematology and Tumor Biology Research, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China.
Yu
Kang
K
Liu
Xin Hua
XH
Yin
Li Hui
LH
Kirschenbaum
Alexander
A
Yao
Shen
S
Narla
Goutham
G
DiFeo
Analisa
A
Wu
Jian Buo
JB
Yuan
Yong
Y
Ho
Shuk-Mei
SM
Lam
Ying Wai
YW
Levine
Alice C
AC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle; D004032:Diet; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D029777:Momordica charantia / Q000737:chemistry*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010940:Plant Proteins / Q000302:isolation & purification / Q000494:pharmacology*; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology*; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054788:Ribosome Inactivating Proteins / Q000302:isolation & purification / Q000494:pharmacology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D056572:Histone Deacetylase Inhibitors; D010940:Plant Proteins; D012333:RNA, Messenger; D008156:Luciferases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; D054788:Ribosome Inactivating Proteins; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases