MicroRNA-19a/b mediates grape seed procyanidin extract-induced anti-neoplastic effects against lung cancer.
Oncomirs are microRNAs (miRNA) associated with carcinogenesis and malignant transformation. They have emerged as potential molecular targets for anti-cancer therapy. We hypothesize that grape seed procyanidin extract (GSE) exerts antineoplastic effects through modulations of oncomirs and their downstream targets. We found that GSE significantly down-regulated oncomirs miR-19a and -19b in a variety of lung neoplastic cells. GSE also increased mRNA and protein levels of insulin-like growth factor II receptor (IGF-2R) and phosphatase and tensin homolog (PTEN), both predicted targets of miR-19a and -19b. Furthermore, GSE significantly increased PTEN activity and decreased AKT phosphorylation in A549 cells. Transfection of miR-19a and -19b mimics reversed the up-regulations of IGF2R and PTEN gene expression and abrogated the GSE induced anti-proliferative response. Additionally, oral administration of leucoselect phytosome, comprised of standardized grape seed oligomeric procyanidins complexed with soy phospholipids, to athymic nude mice via gavage, significantly down-regulated miR-19a, -19b and the miR-17-92 cluster host gene (MIR17HG) expressions, increased IGF-2R, PTEN, decreased phosphorylated-AKT in A549 xenograft tumors, and markedly inhibited tumor growth. To confirm the absorption of orally administered GSE, plasma procyanidin B1 levels, between 60 and 90 min after gavage of leucoselect phytosome (400 mg/kg), were measured by LC/MS at week 2 and 8 of treatment; the estimated concentration that was associated with 50% growth inhibition (IC50) (1.3 μg/mL) in vitro was much higher than the IC50 (0.032-0.13 μg/ml) observed in vivo. Our findings reveal novel antineoplastic mechanisms by GSE and support the clinical translation of leucoselect phytosome as an anti-neoplastic and chemopreventive agent for lung cancer.
Pulmonary, Critical Care, and Sleep Section, New Mexico Veterans Administration Health Care System, University of New, Mexico. Electronic address: jenny.mao@va.gov.
Jenny T
JT
Mao
Pulmonary, Critical Care, and Sleep Section, New Mexico Veterans Administration Health Care System, University of New, Mexico.
Bingye
B
Xue
Pulmonary, Critical Care, and Sleep Section, New Mexico Veterans Administration Health Care System, University of New, Mexico.
Jane
J
Smoake
UCLA Center for Human Nutrition, David Geffen School of Medicine at UCLA.
Qing-Yi
QY
Lu
Pulmonary, Critical Care, and Sleep Section, New Mexico Veterans Administration Health Care System, University of New, Mexico.
Heesung
H
Park
UCLA Center for Human Nutrition, David Geffen School of Medicine at UCLA.
Susanne M
SM
Henning
Pathology and Clinical Laboratory Services, New Mexico Veterans Administration Health Care System, University of New, Mexico.
Windie
W
Burns
Cardiothoracic Surgery Section, New Mexico Veterans Administration Health Care System, University of New, Mexico.
Alvise
A
Bernabei
Department of Biostatistics, Department of Medicine, David Geffen School of Medicine at UCLA.
David
D
Elashoff
Pulmonary & Critical Care Medicine, Scripps Green Hospital.
Kenneth J
KJ
Serio
Pathology and Clinical Laboratory Services, New Mexico Veterans Administration Health Care System, University of New, Mexico.
Larry
L
Massie
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000627:therapeutic use*; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019587:Dietary Supplements; D005260:Female; D056604:Grape Seed Extract / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D007408:Intestinal Absorption; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000819:agonists / Q000378:metabolism; D044945:Proanthocyanidins / Q000378:metabolism / Q000627:therapeutic use*; D012334:RNA, Neoplasm / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011897:Random Allocation; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D056604:Grape Seed Extract; C511402:Grape Seed Proanthocyanidins; C549214:MIRN19A microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D044945:Proanthocyanidins; D012334:RNA, Neoplasm
AKT; Grape seed procyanidin B1 bioavailability; IGF-2R; MiRNA; PTEN