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14-3-3 sigma modulates pancreatic cancer cell survival and invasiveness.

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Call No.	RC280.P25 N48 2008
Author	Neupane, Divas.
Title	14-3-3 sigma modulates pancreatic cancer cell survival and invasiveness.
Date	2008
Abstract	14-3-3 is down-regulated in certain human cancers, but its expression is increased in pancreatic ductal adenocarcinoma (PDAC). The purpose of the present study was to investigate the potential role of 14-3-3σ in PDAC. The levels of 14-3-3 isoforms were determined by real-time quantitative PCR (Q-PCR) in laser-captured normal pancreatic ductal cells and pancreatic cancer cells, and in five pancreatic cancer cell lines. PANC-1 cells, which express very low levels of 14-3-3Σ, were stably transfected with a human 14-3-3σ cDNA. Conversely, in T3M4 cells, the high endogenous level of 14-3-3σ was suppressed by lentivirus mediated delivery of specific shRNA (short hairpin RNA). The consequences on apoptosis and survival in response to cisplatin, motility and invasiveness were then studied. The cancer cells in all seven PDAC samples expressed relatively high level of 14-3-3σ mRNA by Q-PCR, when compared with other members of the 14-3-3 family or with 14-3-3σ mRNA level in normal pancreatic duct cells. The 14-3-3σ protein level was high in BxPC3, COLO-357 and T3M4 cells, intermediate in ASPC-1 cells, and low in PANC-1 cells. With the exception of ASPC-1 cells, all tested cell lines released a detectable amount of 14-3-3σ into conditioned medium. Overexpression of 14-3-3σ in PANC-1 cells led to increased resistance to cisplatin-induced apoptosis, increased basal migration, and increased invasion in response to epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1). By contrast, shRNA mediated knockdown of endogenous 14-3-3σ in T3M4 cells did not alter migration but led to enhanced sensitivity towards cisplatin, increased invasiveness in response to EGF, and decreased invasiveness in response to IGF-1. These findings indicate that 14-3-3σ contributes to the chemoresistance of pancreatic cancer cells, and exerts cell type dependent effects on cell migration and invasion. Therefore, strategies aimed at suppressing 14-3-3σ expression and/or function may have a therapeutic benefit in subgroups of patients with PDAC.
Description	xii, 140 leaves : ill. (some col.) 28 cm.
Format	application/pdf
Advisor	Korc, Murray, Eastman, Alan R., Brenner, Charles, DiRenzo, James, Spinella, Michael J.
Subject	Pancreas -- Cancer -- Pathophysiology. Pancreatic duct -- Pathophysiology. Proteins -- Pathophysiology. 14-3-3 Proteins -- physiology. Pancreatic Neoplasms -- pathology.
College	Dartmouth Medical School -- Department of Pharmacology and Toxicology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.244

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	14-3-3 SIGMA MODULATES PANCREATIC CANCER CELL SURVIVAL AND INVASIVENESS A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmacology and Toxicology by Divas Neupane DARTMOUTH COLLEGE Hanover, New Hampshire November, 2008 Examining Committee: ________________________ (Chair) Murray Korc, M.D. _________________________ Alan R. Eastman, Ph.D. _________________________ Charles Brenner, Ph.D. _________________________ James DiRenzo, Ph.D. _________________________ Michael J. Spinella, Ph.D. _________________________ Brian W. Pogue, Ph.D. Dean of Graduate Studies

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