PI-3′ kinase and NF-κB cross-signaling in human pancreatic cancer cells

Shah, Shimul A.; Potter, Michael W.; Hedeshian, Mohir H.; Kim, Robin D.; Chari, Ravi S.; Callery, Mark P.

doi:10.1016/s1091-255x(01)80102-5

Cited by 38 publications

(14 citation statements)

References 32 publications

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“…Our observation that HMGA1 silencing suppresses Akt activity is significant, as Akt is now recognized as an important mediator of malignant cellular behavior, including the capacity for resisting apoptotic stimuli, in pancreatic adenocarcinoma (43)(44)(45). Trapasso et al have reported that antisense-mediated suppression of HMGA1 expression results in an apoptotic response in three pancreatic cancer cell lines (46).…”

Section: Hmga1 and Pancreatic Adenocarcinoma Invasivenessmentioning

confidence: 62%

HMGA1 Is a Determinant of Cellular Invasiveness and In vivo Metastatic Potential in Pancreatic Adenocarcinoma

2006

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HMGA1 proteins are architectural transcription factors that are overexpressed in a range of human malignancies, including pancreatic adenocarcinoma. We hypothesized that HMGA1 expression is a determinant of cellular invasiveness and metastasis in pancreatic cancer. Stable silencing of HMGA1 in MiaPaCa2 and PANC1 pancreatic adenocarcinoma cells was achieved by transfection of short hairpin RNAgenerating vectors. Additionally, stable overexpression of HMGA1 in MiaPaCa2 cells (characterized by low levels of inherent HMGA1 expression) was achieved. HMGA1 silencing resulted in significant reductions in cellular invasiveness through Matrigel; in cellular matrix metalloproteinase-9 (MMP-9) activity, mRNA levels, and gene promoter activity; and in Akt phosphorylation at Ser 473 . Conversely, forced HMGA1 overexpression resulted in significant increases in cellular invasiveness; in cellular MMP-9 activity, mRNA levels, and promoter activity; and in Akt phosphorylation at Ser 473 . HMGA1 overexpression-induced increases in invasiveness were MMP-9 dependent. The role of phosphatidylinositol-3 kinase (PI3K)/Akt in mediating HMGA1-dependent invasiveness was elucidated by a specific PI3K inhibitor (LY294002) and constitutively active and dominant-negative Akt adenoviral constructs. Akt-dependent modulation of MMP-9 activity contributed significantly to HMGA1 overexpressioninduced increases in invasive capacity. Furthermore, HMGA1 silencing resulted in reductions in metastatic potential and tumor growth in vivo and in tumoral MMP-9 activity. Our findings suggest that HMGA1 may be a novel molecular determinant of invasiveness and metastasis, as well as a potential therapeutic target, in pancreatic adenocarcinoma.

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Section: Hmga1 and Pancreatic Adenocarcinoma Invasivenessmentioning

confidence: 62%

HMGA1 Is a Determinant of Cellular Invasiveness and In vivo Metastatic Potential in Pancreatic Adenocarcinoma

2006

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“…Functionally, the significance of this amplification has been suggested in PDAC cell lines through the use of antisense oligonucleotides, which inhibit the growth of PDAC lines in xenograft assays (Cheng et al 1996). Additionally, pharmacological inhibition of PI3K appears to increase the sensitivity of PDAC cell lines to chemotherapy as well as TNF-␣-induced apoptosis, and diminishes serum-induced proliferation (Ng et al 2000;Perugini et al 2000;Shah et al 2001). The mammalian target of rapamycin (mTOR), which acts downstream of AKT2, has been shown to be activated in PDAC.…”

Section: The K-ras Oncogene and Its Signaling Pathwaysmentioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

Hezel¹,

Kimmelman²,

Stanger³

et al. 2006

Genes Dev.

1,195

925

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Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the UnitedStates with a median survival of <6 mo and a dismal 5-yr survival rate of 3%-5%. The cancer's lethal nature stems from its propensity to rapidly disseminate to the lymphatic system and distant organs. This aggressive biology and resistance to conventional and targeted therapeutic agents leads to a typical clinical presentation of incurable disease at the time of diagnosis. The well-defined serial histopathologic picture and accompanying molecular profiles of PDAC and its precursor lesions have provided the framework for emerging basic and translational research. Recent advances include insights into the cancer's cellular origins, high-resolution genomic profiles pointing to potential new therapeutic targets, and refined mouse models reflecting both the genetics and histopathologic evolution of human PDAC. This confluence of developments offers the opportunity for accelerated discovery and the future promise of improved treatment. Pancreas anatomy and physiologyThe pancreas, an organ of endodermal derivation, is the key regulator of protein and carbohydrate digestion and glucose homeostasis (Fig. 1). The exocrine pancreas (80% of the tissue mass of the organ) is composed of a branching network of acinar and duct cells that produce and deliver digestive zymogens into the gastrointestinal tract. The acinar cells, which are organized in functional units along the duct network, synthesize and secrete zymogens into the ductal lumen in response to cues from the stomach and duodenum. Within the acinar units near the ducts are centroacinar cells. The endocrine pancreas, which regulates metabolism and glucose homeostasis through the secretion of hormones into the bloodstream, is composed of four specialized endocrine cell types gathered together into clusters called Islets of Langerhans.Mirroring the physiologic and cellular diversity of the pancreas is a spectrum of distinct pancreatic malignancies that possess histological and molecular features that recall the characteristics of the various normal cellular constituents. These multiple tumor types and hallmark features are summarized in Table 1. Pancreatic ductal adenocarcinoma (PDAC), whose nomenclature derives from its histological resemblance to ductal cells, is the most common pancreatic neoplasm and accounts for >85% of pancreatic tumor cases (Warshaw and Fernandez-del Castillo 1992;. PDAC is the focus of this review, and the reader is directed to the following excellent review covering other pancreas cancer types (Hruban et al. 2006b). Epidemiology of PDACPDAC is associated with only a few known demographic and environmental risk factors and a handful of autosomal dominant genetic conditions. Multiple studies have established advanced age, smoking, and long-standing chronic pancreatitis as clear risk factors; diabetes and obesity also appear to confer increased risk (Everhart and Wright 1995;Fuchs et al. 1996;Gapstur et al. 2000;Michaud et al. 2001;Berrington de Gonzal...

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“…Although molecular mechanisms linking PI3K signaling to the cell cycle are not fully understood in PDAC cells, the control of the G 1 -S phase progression was shown to depend on PI3K signaling (14,18). The transcription factors c-myc and NF-nB were shown to be downstream targets of the PI3K pathway in PDAC (11,19,20).…”

Section: Introductionmentioning

confidence: 99%

Phosphoinositide-3-Kinase Signaling Controls S-Phase Kinase–Associated Protein 2 Transcription via E2F1 in Pancreatic Ductal Adenocarcinoma Cells

et al. 2007

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The phosphoinositide-3-kinase (PI3K)/AKT signaling pathway controls fundamental processes of cancer cell biology like proliferation and cell survival. The PI3K/AKT pathway is activated in pancreatic ductal adenocarcinoma (PDAC) cells. The molecular mechanisms linking PI3K signaling to the cell cycle machinery in PDAC cells are not investigated in detail. Using the PI3K inhibitor Ly294002 as well as small interfering RNA targeting AKT1 expression, we show that PI3K controls the proliferation and G 1 phase progression of PDAC cells. Gene profiling revealed several important regulators of G 1 -S phase progression controlled by PI3K signaling like p21Cip1 , S-phase kinase-associated protein 2 (SKP2), CDC25a, cyclin A, cyclin D2, CDK2, and cyclin E. We show that the F-box protein SKP2, an oncogene up-regulated in PDAC, is transcriptionally regulated by the PI3K/AKT1 pathway in PDAC cells. At the molecular level, the control of the SKP2 gene by PI3K is due to the regulation of E2F1 binding to the proximal SKP2 gene promoter. The complex and profound connection of PI3K/ AKT1 signaling to the cell cycle qualifies this pathway as a suitable target for therapeutic intervention in PDAC. [Cancer Res 2007;67(9):4149-56]

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PI-3′ kinase and NF-κB cross-signaling in human pancreatic cancer cells

Cited by 38 publications

References 32 publications

HMGA1 Is a Determinant of Cellular Invasiveness and In vivo Metastatic Potential in Pancreatic Adenocarcinoma

HMGA1 Is a Determinant of Cellular Invasiveness and In vivo Metastatic Potential in Pancreatic Adenocarcinoma

Genetics and biology of pancreatic ductal adenocarcinoma

Phosphoinositide-3-Kinase Signaling Controls S-Phase Kinase–Associated Protein 2 Transcription via E2F1 in Pancreatic Ductal Adenocarcinoma Cells

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