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Akt3 controls vascular endothelial growth factor secretion and angiogenesis in ovarian cancer cells.

ABSTRACT: The PI3 kinase/Akt pathway is commonly deregulated in human cancers, functioning in such processes as proliferation, glucose metabolism, survival and motility. We have previously described a novel function for one of the Akt isoforms (Akt3) in primary endothelial cells: the control of VEGF-induced mitochondrial biogenesis. We sought to determine if Akt3 played a similar role in carcinoma cells. Because the PI3 kinase/Akt pathway has been strongly implicated as a key regulator in ovarian carcinoma, we tested the role of Akt3 in this tumor type. Silencing of Akt3 by shRNA did not cause an overt reduction in mitochondrial gene expression in a series of PTEN positive ovarian cancer cells. Rather, we find that blockade of Akt3, results in smaller, less vascularized tumors in a xenograft mouse model that is correlated with a reduction in VEGF expression. We find that blockade of Akt3, but not Akt1, results in a reduction in VEGF secretion and retention of VEGF protein in the endoplasmic reticulum (ER). The reduction in secretion under conditions of Akt3 blockade is, at least in part, due to the down regulation of the resident golgi protein and reported tumor cell marker, RCAS1. Conversely, over-expression of Akt3 results in an increase in RCAS1 expression and in VEGF secretion. Silencing of RCAS1 using siRNA inhibits VEGF secretion. These findings suggest an important role for Akt3 in the regulation of RCAS1 and VEGF secretion in ovarian cancer cells.

SUBMITTER: Liby TA

PROVIDER: S-EPMC3189303 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Akt3 controls vascular endothelial growth factor secretion and angiogenesis in ovarian cancer cells.

Liby Tiera A TA Spyropoulos Perry P Buff Lindner Haley H Eldridge Juanita J Beeson Craig C Hsu Tien T Muise-Helmericks Robin C RC

International journal of cancer 20110420 3

The PI3 kinase/Akt pathway is commonly deregulated in human cancers, functioning in such processes as proliferation, glucose metabolism, survival and motility. We have previously described a novel function for one of the Akt isoforms (Akt3) in primary endothelial cells: the control of VEGF-induced mitochondrial biogenesis. We sought to determine if Akt3 played a similar role in carcinoma cells. Because the PI3 kinase/Akt pathway has been strongly implicated as a key regulator in ovarian carcinom ...[more]

PMID: 21351097

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Project description:Which receptors for prostaglandin E2 (PGE2) and vascular endothelial growth factor A (VEGFA) mediate angiogenesis in the human follicle around the time of ovulation?PGE2 and VEGFA act via multiple PGE2 receptors (PTGERs) and VEGF receptors (VEGFRs) to play complementary roles in follicular angiogenesis.Production of PGE2 and VEGFA by the follicle are prerequisites for ovulation. PGE2 is an emerging regulator of angiogenesis and has not been examined in the context of the human ovulatory follicle. VEGFA is an established regulator of follicular angiogenesis.Ovarian biopsies containing the ovulatory follicle were obtained from 11 women of reproductive age (30-45 years) undergoing surgery for laparoscopic sterilization. In some cases, women received hCG to substitute for the ovulatory LH surge before ovarian biopsy. In addition, aspirates from four women of reproductive age (18-31 years) undergoing gonadotrophin stimulation for oocyte donation were obtained for isolation of human ovarian microvascular endothelial cells (hOMECs).Ovarian biopsies were utilized for immunocytochemical detection of von Willebrand factor to identify endothelial cells. hOMECs were cultured with PGE2, PTGER receptor selective agonists, VEGFA, or VEGFR selective agonists. hOMECs were assessed for proliferation by Ki67 immunocytochemistry. hOMEC migration was determined by counting cells which migrated through a porous membrane in vitro. Sprout formation was quantified by determining sprout number and length from photographs take after culture of hOMECs in a 3-dimensional matrix.Endothelial cells were not observed within the granulosa cell layer of human ovulatory follicles prior to an ovulatory dose of hCG and were first seen amongst granulosa cells 18-34 h after hCG. In vitro, PGE2 enhanced migration and sprout formation but did not alter hOMEC proliferation. Agonists selective for each PTGER increased migration with no change in proliferation. PTGER1 and PTGER2 agonists increased the number of sprouts, while only PTGER1 affected sprout length. VEGFA increased hOMEC proliferation, migration, and formation of structures resembling capillary sprouts. Signaling through VEGFR1 promoted hOMEC migration, proliferation, and the formation of few, long endothelial cell sprouts, while VEGFR2 stimulation promoted hOMEC migration and the formation of many, short sprouts. All effects of treatments in vitro were considered significant at P < 0.05.While primary cultures of hOMECs respond to PGE2 and VEGFA differently than other cultured endothelial cells, hOMECs may not respond to PGE2 and VEGFA in vivo as they do in vitro.Agonists and antagonists selective for PTGER1, PTGER2, VEGFR1, or VEGFR2 may have therapeutic value to promote or prevent ovulation in women.This research was supported by grant funding from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development (HD071875 to D.M.D., T.E.C., M.B.). The authors have no conflicts of interest to disclose.

Dataset Information

Akt3 controls vascular endothelial growth factor secretion and angiogenesis in ovarian cancer cells.

Publications

Akt3 controls vascular endothelial growth factor secretion and angiogenesis in ovarian cancer cells.

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