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Tumor Biology |
Human Genetics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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IGF-IR,3
a member of the tyrosine kinase family, is a heterotetramer consisting
of 
- and ß-subunits (2)
. The -subunits function in
ligand binding, whereas the ß-subunits span the plasma membrane and
transmit cellular signals. Numerous studies have demonstrated that
overexpression and excessive activation of IGF-IR are associated with
malignant transformation, increased tumor aggressiveness, and
protection from apoptosis (2, 3, 4, 5, 6)
. It also has been
reported that IGF-IR is often overexpressed in human pancreatic tumors
(7)
. In experiments using pancreatic cancer cell lines
overexpressing IGF-IR, cell growth was significantly inhibited by an
anti-IGF-IR antibody or IGF-IR antisense oligodeoxynucleotides
(7)
. Thus, IGF-IR may play a critical role in the growth
of pancreatic cancer cells.
AKT (also known as protein kinase B) consists of a family of highly conserved serine/threonine kinases including AKT1 and AKT2. These kinases are activated in response to a wide variety of growth factors through PI3K (8, 9, 10) . The pleckstrin homology domain of AKT has an affinity for PtdIns-3,4-P2 and PtdIns-3,4,5-P3 produced by PI3K (11 , 12) . PtdIns-3,4-P2 and/or PtdIns-3,4,5-P3 trigger the translocation of AKT to the plasma membrane, where the AKT kinases can be activated by phosphorylation of Thr-308/309 and Ser-473/474 (13) . Activated AKT has been shown to mediate cell survival by phosphorylating several downstream targets, such as BAD (14) and caspase-9 (15) . In contrast, the tumor suppressor PTEN inhibits PI3K-dependent activation of AKT by dephosphorylating PtdIns-3,4-P2 and PtdIns-3,4,5-P3 (16) .
The nonreceptor tyrosine kinase Src has been reported to be overexpressed and activated in most pancreatic tumors and pancreatic cancer cell lines (17) . Furthermore, active Src has been shown to increase IGF-I-dependent growth of PANC-1 cells through the up-regulation of IGF-IR expression (18) . However, downstream targets of active Src that regulate IGF-IR expression have not been identified to date. In other cell signaling pathways, Src has been shown to activate AKT through PI3K (19) . In particular, AKT2 is a potentially intriguing target because we and others have reported previously amplification and overexpression of the AKT2 oncogene in 10–20% of pancreatic tumors and cell lines (20, 21, 22) .
We report here that AKT, specifically AKT1 or AKT2, up-regulates the expression of IGF-IR, and inactivation of AKT signaling inhibits expression of IGF-IR. We also show that increased IGF-IR expression induced by active AKT markedly enhances the invasiveness of human pancreatic cancer cells.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Antibodies.
Antibodies used for immunoprecipitation and Western blotting were as
follows. Anti-AKT1, anti-AKT2, and anti-Src antibodies were obtained
from Upstate Biotechnology (Lake Placid, NY); anti--subunit of
IGF-IR, anti-ß-subunit of IGF-IR, and anti-PTEN antibodies were from
Santa Cruz Biotechnology (Santa Cruz, CA); anti-HA antibody was from
Babco (Richmond, CA); anti-FLAG-M2 antibody was from Eastman Kodak; and
anti-pan Ras antibody was from Oncogene Science (Cambridge, MA).
Plasmid Constructs and Transient Transfection Assays.
HA epitope-tagged AKT1 (HA-AKT1) and
AKT2 (HA-AKT2) cDNAs were constructed by PCR
using pcDNA3 expression vector (Invitrogen, Carlsbad, CA). Flag
epitope-tagged AKT1 (Flag-AKT1) and
AKT2 (Flag-AKT2) were prepared using the same
vector. Constitutively active HA-AKT1
(myr-HA-AKT1) and HA-AKT2
(myr-HA-AKT2) were created by adding a double-stranded DNA
fragment corresponding to a myristylation signal at the 5' end of each
cDNA. Myr-HA-EGFP-AKT1 and myr-HA-EGFP-AKT2 were
also generated. Wild-type Src (c-Src), active
Src (SrcY527F), dominant-negative Src
(N17Src), and active Ras (v-Ha-ras)
were a kind gift from Dr. C. Patriotis (Fox Chase Cancer Center).
Cells were plated at a density of 2 x 105 cells/well in six-well plates 1 day before transfection. Transient transfection of the cells was carried out with 2 µg of DNA/well using GenePORTER (Gene Therapy Systems, San Diego, CA), according to the protocol suggested by the manufacturer. Transfection efficiencies were determined by immunocytochemistry, using anti-HA antibody, and nuclear counterstaining with diamidino-2-phenylindole. Transfection efficiencies in all experiments were consistently >40%.
In Vitro AKT Kinase Assay.
Cells transiently transfected with the expression construct of
Flag-AKT were washed once with ice-cold PBS and lysed with
lysis buffer [50 mM Tris-HCl (pH 7.5), 137
mM sodium chloride, 1 mM
EDTA, 1% NP40, 10% glycerol, 0.1 mM sodium
orthovanadate, 10 mM sodium
PPi, 20 mM
ß-glycerophosphate, 50 mM sodium fluoride, 1
mM phenylmethylsulfonyl fluoride, 2
µM leupeptin, and 2 µg/ml aprotinin].
Insoluble material was removed by centrifugation at 4°C for 10 min at
18,400 x g. The supernatants were incubated
with monoclonal anti-FLAG M2 antibody at 4°C for 1 h. The
immunocomplex was precipitated with protein A:protein G (1:1) agarose
beads (Life Technologies, Inc., Grand Island, NY) at 4°C for 1 h
and washed twice with lysis buffer. The immunoprecipitates were
incubated with 5 µCi of [
-32P]ATP in
kinase buffer [20 mM HEPES (pH 7.4), 10
mM MgCl2, and 10
mM MnCl2] at 30°C for 25
min using histone H2B as a substrate. The reactions were terminated by
addition of 2x Laemmli sample loading buffer and then subjected to
15% SDS-PAGE. Phosphorylation of histone H2B was visualized by
autoradiography.
Immunoprecipitation and Western Blot Analysis.
At 48 h after transfection, cells were washed with ice-cold PBS
and lysed with lysis buffer as described above. Protein concentration
was determined with a Bio-Rad Protein Assay Kit (Bio-Rad, Hercules,
CA). For immunoprecipitation, cell lysates (200 µg of protein) were
incubated with 0.5 µg of anti--subunit of IGF-IR for 1 h at
4°C. After incubation with protein A:protein G (1:1) agarose beads
for 1 h at 4°C, immunoprecipitates were washed three times with
lysis buffer. Proteins were subjected to 6% SDS-PAGE and Western
blotting. Membranes were blocked and incubated with anti-ß-subunit of
IGF-IR antibody (1:400) in Tris-buffered saline containing 1% nonfat
dry milk/0.1% Tween 20. Detection of antigen-bound antibody was
carried out with Renaissance Chemiluminescence Reagent Plus (NEN Life
Science, Boston, MA).
In Vitro Cell Invasion Assay Using Matrigel.
Cell invasion assays were performed using Transwell membrane filter
inserts with 8-µm pore size (Corning Costar, Cambridge, MA). The
upper surface of the Transwell membrane was coated with 250 µg/ml of
growth factor-reduced Matrigel matrix (Becton Dickinson, Bedford, MA)
overnight at 4°C, rehydrated once with 0.1% BSA in DMEM for 1 h
at room temperature, and then placed in the upper compartment of
six-well tissue culture plates. Twenty-four h after transfection with
myr-HA-EGFP-AKT, PANC-1 cells were removed from tissue
culture flasks by a short exposure to 5 mM EDTA
and washed once in PBS. Then 2 x 105 cells in serum-free medium containing 0.1%
BSA were added to each Transwell chamber and allowed to migrate toward
the underside of the membrane for 18 h with and without 20 ng/ml
of IGF-I (Life Technologies) in the lower chamber as a chemoattractant.
After cells were fixed in 3.5% paraformaldehyde, cells on the upper
surface of the membrane were removed by wiping with a cotton swab, and
membranes were mounted onto glass slides. The relative number of
invasion was determined by counting the number of invading
EGFP-positive cells. The number of invading cells transfected with
empty vector was assigned a value of 1.0 in each experiment. Twenty
random fields/membrane were counted for each assay. Each determination
represents the average of three separate experiments.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, cells transfected with active Src had
significantly more IGF-IR protein than cells transfected with vector
alone.
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. The amount of IGF-IR protein in
wild-type AKT-transfected cells was comparable with that of
active Src-transfected cells, whereas IGF-IR expression was markedly
higher in cells transfected with constitutively active AKT.
These data suggest that activation of AKT is associated with the
up-regulation of IGF-IR expression. AKT1 and AKT2 appear to be equally
capable of inducing increased amounts of IGF-IR protein, because no
significant difference in IGF-IR expression was observed in cells
transfected with AKT1 or AKT2 constructs.
We also examined the effects of active Src and AKT on the expression of
IGF-IR in AsPC-1 cells. IGF-IR expression was elevated in AsPC-1 cells
transfected with constitutively active AKT1 and
AKT2 (Fig. 1B)
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AKT Is Activated by Active Src.
AKT is activated by various extracellular stimuli through the PI3K
pathway (8, 9, 10)
. To determine whether AKT functions as a
downstream effector of active Src to regulate IGF-IR expression, we
examined whether AKT is activated by active Src in PANC-1 cells. We
assayed the in vitro kinase activity of AKT1 and AKT2 in
cells cotransfected with Flag-AKT constructs and active,
wild-type, or dominant-negative Src. Cells cotransfected
with Flag-AKT and v-Ha-ras served as a positive
control. As shown in Fig. 2
, both AKT1 and AKT2 were activated by active Src or active Ras in
PANC-1 cells. This suggests that AKT functions as a downstream effector
of Src and Ras signaling in these cells. Furthermore, both AKT1 and
AKT2 kinase activities were inhibited by dominant-negative Src (N17Src)
or PTEN, a known inhibitor of PI3K/AKT signaling (16)
.
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, dominant-negative Src and PTEN inhibit the
activation of AKT. We examined PANC-1 cells cotransfected with
AKT and dominant-negative Src to determine
whether dominant-negative Src inhibits the up-regulation of IGF-IR
expression. Indeed, dominant-negative Src blocked induction of IGF-IR
expression in cells cotransfected with wild-type AKT (Fig. 3)
. However, IGF-IR expression was only slightly down-regulated by
dominant-negative Src in cells transfected with constitutively active
AKT. These results suggest that Src activates AKT, which
results in the up-regulation of IGF-IR expression in these cells.
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. In addition,
IGF-IR expression induced by active Src was shown to be inhibited by
PTEN. These data provide further evidence that Src-induced
up-regulation of IGF-IR expression is mediated through the PI3K/AKT
signal transduction pathway.
PANC-1 Cells Transfected with Constitutively Active AKT Have
Increased Invasiveness.
It has been reported that increased expression of IGF-IR in tumorigenic
cells can enhance their invasiveness (23
, 24)
. We
performed an in vitro cell invasion assay using Matrigel
matrix to examine whether the invasiveness of PANC-1 cells transfected
with constitutively active AKT increases via up-regulation
of IGF-IR expression. PANC-1 cells were transiently transfected with
EGFP-containing myr-HA-AKT constructs, i.e.,
myr-HA-EGFP-AKT1 and myr-HA-EGFP-AKT2 (Fig. 4A)
. As a control, cells were transfected with a myristylated
HA-tagged EGFP construct. Transfected cells were easily distinguished
from untransfected cells based on the expression of EGFP. In
vitro kinase assays were used to assess the activity of
myristylated AKT1 and AKT2. Extremely high kinase activity was observed
in both myr-HA-EGFP-AKT1 and
myr-HA-EGFP-AKT2-transfected cells without stimulation,
whereas control vector (myr-HA-EGFP)-transfected cells exhibited low
kinase activity (Fig. 4A)
. IGF-IR expression also was
elevated in myr-HA-EGFP-AKT-transfected PANC-1 cells as
detected by Western blotting (data not shown). Migratory cells were
identified by counting the number of EGFP-positive cells on the
underside of the Transwell membrane. Repeated experiments revealed that
constitutively active AKT-transfected cells showed
significantly higher invasiveness potential than cells transfected with
vector alone (Fig. 4, B and C)
. Without IGF-I in
the lower chamber, there were no significant differences in
invasiveness potential between constitutively active AKT-
and vector-transfected cells. These results suggest that constitutively
active AKT enhances the invasiveness of tumorigenic cells through the
up-regulation of IGF-IR expression.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, in which we propose that AKT participates in a feed-back loop whereby
activation of AKT up-regulates IGF-IR expression. The increased IGF-IR
is available to interact with the ligand IGF-I, and IGF-I binding to
IGF-IR further activates the PI3K/AKT signaling pathway.
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In human pancreatic cancer, it has been reported that IGF-I is not expressed in cancer cells and that IGF-I is abundantly expressed in the stromal tissue surrounding the tumor cells (7) . This suggests that IGF-I exerts a paracrine effect on pancreatic cancer cell growth. IGF-I has been shown to be expressed in hepatocytes (32) . Thus, paracrine growth stimulation by hepatocyte-derived IGF-I may account, at least in part, for the fact that pancreatic cancer cells readily metastasize to the liver at early stages of the disease. In addition, it has been shown that IGF-I stimulates the invasion and metastasis of cancer cells (33, 34, 35) , and that increased expression of IGF-IR in tumorigenic cells could enhance their invasiveness (23) . We demonstrated that PANC-1 cells transfected with constitutively active AKT1 and AKT2 show increased invasiveness in the presence of IGF-I. This observation further supports our contention that activation of AKT up-regulates IGF-IR expression and demonstrates that increased IGF-IR expression induced by active AKT is sufficient to enhance the invasiveness of pancreatic cancer cells in the presence of IGF-I. In this study, we used Matrigel matrix to assay for invasiveness potential. Matrigel contains ECM components such as laminin and collagen IV (36 , 37) , which closely resemble the tumor environment. It has been suggested that IGF-IR and IGF-I regulate the expression of ECM proteinases, such as matrix metalloproteinases and/or urokinase-type plasminogen activator, to enhance invasiveness potential (24 , 38) . These ECM proteinases are directly or indirectly involved in degrading the ECM. Indeed, urokinase-type plasminogen activator (39 , 40) or activated forms of matrix metalloproteinases (41 , 42) are detectable in human pancreatic cancer and/or its metastatic outgrowths. We reported previously that expression of AKT2 in PANC-1 and AsPC-1 cells is greatly decreased by antisense AKT2 RNA, and that tumorigenicity in nude mice and tumor cell invasiveness are diminished in cells expressing antisense AKT2 RNA (20) . Taken together, our data suggest that overexpression and activation of AKT plays a significant role in the invasiveness of pancreatic cancer cells. Likewise, other investigators have reported that activation of PI3K signaling is implicated in hepatocyte growth factor-dependent invasiveness, and inactivation of PI3K results in reduced invasiveness of human intestinal cells (43) .
The fact that inactivation of AKT can down-regulate IGF-IR expression suggests that AKT could represent an important therapeutic target in human pancreatic cancer. Because amplification and overexpression of AKT2 have been reported in pancreatic cancers, perturbations of the AKT2 kinase may play a significant role in the pathogenesis of such tumors (20, 21, 22) . Thus, selective inhibitors that specifically target downstream effectors of AKT to regulate IGF-IR expression may have important therapeutic implications in pancreatic cancer.
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FOOTNOTES |
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1 Supported by National Cancer Institute Grants
CA77429 and CA06927 and by an appropriation from the Commonwealth of
Pennsylvania. 
2 To whom requests for reprints should be
addressed, at Fox Chase Cancer Center, 7701 Burholme Avenue,
Philadelphia, PA 19111. Phone: (215) 728-2610; Fax: (215) 728-2741.
3 The abbreviations used are: IGF-IR, IGF-I
receptor; IGF-I, insulin-like growth factor I; PI3K,
phosphatidylinositol 3-kinase; PtdIns-3,4-P2,
phosphatidylinositol-3,4-bisphosphate; PtdIns-3,4,5-P3,
phosphatidylinositol-3,4,5-trisphosphate; PTEN, phosphatase and tensin
homologue deleted on chromosome 10; HA, hemagglutinin; EGFP, enhanced
green fluorescent protein; ECM, extracellular matrix.
Received 6/20/00. Accepted 11/13/00.
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Y. Min, Y. Adachi, H. Yamamoto, H. Ito, F. Itoh, C.-T. Lee, S. Nadaf, D. P. Carbone, and K. Imai Genetic Blockade of the Insulin-like Growth Factor-I Receptor: A Promising Strategy for Human Pancreatic Cancer Cancer Res., October 1, 2003; 63(19): 6432 - 6441. [Abstract] [Full Text] [PDF]
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G. Zhang, B. He, and G. F. Weber Growth Factor Signaling Induces Metastasis Genes in Transformed Cells: Molecular Connection between Akt Kinase and Osteopontin in Breast Cancer Mol. Cell. Biol., September 15, 2003; 23(18): 6507 - 6519. [Abstract] [Full Text] [PDF]
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 O. Stoeltzing, W. Liu, N. Reinmuth, F. Fan, A. A. Parikh, C. D. Bucana, D. B. Evans, G. L. Semenza, and L. M. Ellis Regulation of Hypoxia-Inducible Factor-1{alpha}, Vascular Endothelial Growth Factor, and Angiogenesis by an Insulin-Like Growth Factor-I Receptor Autocrine Loop in Human Pancreatic Cancer Am. J. Pathol., September 1, 2003; 163(3): 1001 - 1011. [Abstract] [Full Text] [PDF]
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S. J. Grille, A. Bellacosa, J. Upson, A. J. Klein-Szanto, F. van Roy, W. Lee-Kwon, M. Donowitz, P. N. Tsichlis, and L. Larue The Protein Kinase Akt Induces Epithelial Mesenchymal Transition and Promotes Enhanced Motility and Invasiveness of Squamous Cell Carcinoma Lines Cancer Res., May 1, 2003; 63(9): 2172 - 2178. [Abstract] [Full Text] [PDF]
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 K. M. Woods Ignatoski, D. L. Livant, S. Markwart, N. K. Grewal, and S. P. Ethier The Role of Phosphatidylinositol 3'-Kinase and Its Downstream Signals in erbB-2-Mediated Transformation Mol. Cancer Res., May 1, 2003; 1(7): 551 - 560. [Abstract] [Full Text] [PDF]
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 S. Marino, P. Krimpenfort, C. Leung, H. A. G. M. van der Korput, J. Trapman, I. Camenisch, A. Berns, and S. Brandner PTEN is essential for cell migration but not for fate determination and tumourigenesis in the cerebellum Development, March 9, 2003; 129(14): 3513 - 3522. [Abstract] [Full Text] [PDF]
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M. J. Arboleda, J. F. Lyons, F. F. Kabbinavar, M. R. Bray, B. E. Snow, R. Ayala, M. Danino, B. Y. Karlan, and D. J. Slamon Overexpression of AKT2/Protein Kinase B{beta} Leads to Up-Regulation of {beta}1 Integrins, Increased Invasion, and Metastasis of Human Breast and Ovarian Cancer Cells Cancer Res., January 1, 2003; 63(1): 196 - 206. [Abstract] [Full Text] [PDF]
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K. Nakanishi, M. Sakamoto, J. Yasuda, M. Takamura, N. Fujita, T. Tsuruo, S. Todo, and S. Hirohashi Critical Involvement of the Phosphatidylinositol 3-Kinase/Akt Pathway in Anchorage-independent Growth and Hematogeneous Intrahepatic Metastasis of Liver Cancer Cancer Res., May 1, 2002; 62(10): 2971 - 2975. [Abstract] [Full Text] [PDF]
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B.-K. Park, X. Zeng, and R. I. Glazer Akt1 Induces Extracellular Matrix Invasion and Matrix Metalloproteinase-2 Activity in Mouse Mammary Epithelial Cells Cancer Res., October 1, 2001; 61(20): 7647 - 7653. [Abstract] [Full Text] [PDF]
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J. R. Testa and A. Bellacosa AKT plays a central role in tumorigenesis PNAS, September 25, 2001; 98(20): 10983 - 10985. [Full Text] [PDF]
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 D. KIM, S. KIM, H. KOH, S.-O. YOON, A.-S. CHUNG, K. S. CHO, and J. CHUNG Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production FASEB J, September 1, 2001; 15(11): 1953 - 1962. [Abstract] [Full Text] [PDF]
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, invasiveness without
addition of IGF-I; 
, cells treated with IGF-I. Bars,
SD.