PMID- 26657155
OWN - NLM
STAT- MEDLINE
DCOM- 20170901
LR  - 20220316
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 35
IP  - 31
DP  - 2016 Aug 4
TI  - Overexpression of GAB2 in ovarian cancer cells promotes tumor growth and 
      angiogenesis by upregulating chemokine expression.
PG  - 4036-47
LID - 10.1038/onc.2015.472 [doi]
AB  - We previously found that the scaffold adapter GRB2-associated binding protein 2 
      (GAB2) is amplified and overexpressed in a subset of primary high-grade serous 
      ovarian cancers and cell lines. Ovarian cancer cells overexpressing GAB2 are 
      dependent on GAB2 for activation of the phosphatidylinositol 3-kinase (PI3K) 
      pathway and are sensitive to PI3K inhibition. In this study, we show an important 
      role of GAB2 overexpression in promoting tumor angiogenesis by upregulating 
      expression of multiple chemokines. Specifically, we found that suppression of 
      GAB2 by inducible small hairpin RNA in ovarian cancer cells inhibited tumor cell 
      proliferation, angiogenesis and peritoneal tumor growth in immunodeficient mice. 
      Overexpression of GAB2 upregulated the secretion of several chemokines from 
      ovarian cancer cells, including CXCL1, CXCL2 and CXCL8. The secreted chemokines 
      not only signal through endothelial CXCR2 receptor in a paracrine manner to 
      promote endothelial tube formation, but also act as autocrine growth factors for 
      GAB2-induced transformation of fallopian tube secretory epithelial cells and 
      clonogenic growth of ovarian cancer cells overexpressing GAB2. Pharmacological 
      inhibition of inhibitor of nuclear factor kappa-B kinase subunit beta (IKKbeta), but 
      not PI3K, mechanistic target of rapamycin (mTOR) or mitogen-activated protein 
      kinase (MEK), could effectively suppress GAB2-induced chemokine expression. 
      Inhibition of IKKbeta augmented the efficacy of PI3K/mTOR inhibition in suppressing 
      clonogenic growth of ovarian cancer cells with GAB2 overexpression. Taken 
      together, these findings suggest that overexpression of GAB2 in ovarian cancer 
      cells promotes tumor growth and angiogenesis by upregulating expression of CXCL1, 
      CXCL2 and CXCL8 that is IKKbeta-dependent. Co-targeting IKKbeta and PI3K pathways 
      downstream of GAB2 might be a promising therapeutic strategy for ovarian cancer 
      that overexpresses GAB2.
FAU - Duckworth, C
AU  - Duckworth C
AD  - Department of Pathology and Laboratory Medicine, Medical University of South 
      Carolina, Charleston, SC, USA.
AD  - Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 
      USA.
AD  - Center for Genomic Medicine, Medical University of South Carolina, Charleston, 
      SC, USA.
FAU - Zhang, L
AU  - Zhang L
AD  - Department of Pathology and Laboratory Medicine, Medical University of South 
      Carolina, Charleston, SC, USA.
AD  - Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 
      USA.
AD  - Center for Genomic Medicine, Medical University of South Carolina, Charleston, 
      SC, USA.
FAU - Carroll, S L
AU  - Carroll SL
AD  - Department of Pathology and Laboratory Medicine, Medical University of South 
      Carolina, Charleston, SC, USA.
AD  - Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 
      USA.
AD  - Center for Genomic Medicine, Medical University of South Carolina, Charleston, 
      SC, USA.
FAU - Ethier, S P
AU  - Ethier SP
AD  - Department of Pathology and Laboratory Medicine, Medical University of South 
      Carolina, Charleston, SC, USA.
AD  - Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 
      USA.
AD  - Center for Genomic Medicine, Medical University of South Carolina, Charleston, 
      SC, USA.
FAU - Cheung, H W
AU  - Cheung HW
AD  - Department of Pathology and Laboratory Medicine, Medical University of South 
      Carolina, Charleston, SC, USA.
AD  - Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 
      USA.
AD  - Center for Genomic Medicine, Medical University of South Carolina, Charleston, 
      SC, USA.
LA  - eng
GR  - R03 CA139313/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20151214
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Chemokine CXCL1)
RN  - 0 (Chemokine CXCL2)
RN  - 0 (Chemokines)
RN  - 0 (GAB2 protein, human)
RN  - 0 (Interleukin-8)
RN  - 0 (NF-kappa B)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/*physiology
MH  - Animals
MH  - Chemokine CXCL1/genetics
MH  - Chemokine CXCL2/genetics
MH  - Chemokines/*genetics
MH  - Endothelial Cells/physiology
MH  - Female
MH  - Humans
MH  - I-kappa B Kinase/physiology
MH  - Interleukin-8/genetics
MH  - Mice
MH  - NF-kappa B/physiology
MH  - Neovascularization, Pathologic/*etiology
MH  - Ovarian Neoplasms/blood supply/*pathology
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
MH  - Up-Regulation
PMC - PMC4977484
EDAT- 2015/12/15 06:00
MHDA- 2017/09/02 06:00
PMCR- 2016/08/09
CRDT- 2015/12/15 06:00
PHST- 2015/05/04 00:00 [received]
PHST- 2015/11/12 00:00 [revised]
PHST- 2015/11/14 00:00 [accepted]
PHST- 2015/12/15 06:00 [entrez]
PHST- 2015/12/15 06:00 [pubmed]
PHST- 2017/09/02 06:00 [medline]
PHST- 2016/08/09 00:00 [pmc-release]
AID - onc2015472 [pii]
AID - 10.1038/onc.2015.472 [doi]
PST - ppublish
SO  - Oncogene. 2016 Aug 4;35(31):4036-47. doi: 10.1038/onc.2015.472. Epub 2015 Dec 14.