Chronic pancreatitis, pancreatic adenocarcinoma and the black box in-between

Jura, Natalia; Archer, Herbert; Bar–Sagi, Dafna

doi:10.1038/sj.cr.7290269

Cited by 74 publications

(59 citation statements)

References 35 publications

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“…However, it has been estimated that only approximately 25-30% of pancreatic cancer cases in the United States are related to cigarette smoking (6,9). Other factors such as diabetes mellitus, alcohol consumption, and chronic pancreatitis have also been examined for a relationship to pancreatic cancer (5,9,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). However, to our knowledge, no research has been done to determine whether the associated risk of each factor varied by sex.…”

Section: Introductionmentioning

confidence: 99%

Risk Factors for Pancreatic Cancer: Case-Control Study

Hassan¹,

Bondy²,

Wolff³

et al. 2007

Am J Gastroenterology

294

254

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OBJECTIVES-Although cigarette smoking is the most well-established environmental risk factor for pancreatic cancer, the interaction between smoking and other risk factors has not been assessed. We evaluated the independent effects of multiple risk factors for pancreatic cancer and determined whether the magnitude of cigarette smoking was modified by other risk factors in men and women.METHODS-We conducted a hospital-based case-control study involving 808 patients with pathologically diagnosed pancreatic cancer and 808 healthy frequency-matched controls. Information on risk factors was collected by personal interview, and unconditional logistic regression was used to determine adjusted odds ratios (AORs) by the maximum-likelihood method.RESULTS-Cigarette smoking, family history of pancreatic cancer, heavy alcohol consumption (>60 mL ethanol/day), diabetes mellitus, and history of pancreatitis were significant risk factors for pancreatic cancer. We found synergistic interactions between cigarette smoking and family history of pancreatic cancer (AOR 12.8, 95% confidence interval [CI] 1.6-108.9) and diabetes mellitus (AOR 9.3, 95% CI 2.0-44.1) in women, according to an additive model. Approximately 23%, 9%, 3%, and 5% of pancreatic cancer cases in this study were related to cigarette smoking, diabetes mellitus, heavy alcohol consumption, and family history of pancreatic cancer, respectively. CONCLUSIONS-The significant synergy between these risk factors suggests a common pathway for carcinogenesis of the pancreas. Determining the underlying mechanisms for such synergies may lead to the development of pancreatic cancer prevention strategies for high-risk individuals.

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Section: Introductionmentioning

confidence: 99%

Risk Factors for Pancreatic Cancer: Case-Control Study

Hassan¹,

Bondy²,

Wolff³

et al. 2007

Am J Gastroenterology

294

254

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“…Association between chronic inflammation and the development of cancer has been recognized for several years (14)(15)(16)(17)(18). Various cytokines, such as tumor necrosis factor-a (TNF-a) and interleukin-1 (IL-1), which seem to play roles in inflammatory responses and the fibrotic reaction, are overexpressed in pancreatic cancer (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Nuclear Factor-κB Contributes to Hedgehog Signaling Pathway Activation through Sonic Hedgehog Induction in Pancreatic Cancer

Nakashima¹,

Nakamura²,

Yamaguchi³

et al. 2006

Cancer Research

179

129

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The hedgehog (Hh) signaling pathway, which functions as an organizer in embryonic development, is implicated in the development of various tumors. In pancreatic cancer, pathway activation is reported to result from aberrant expression of the ligand, sonic Hh (Shh). However, the details of the mechanisms regulating Shh expression are not yet known. We hypothesized that nuclear factor-KB (NF-KB), a hallmark transcription factor in inflammatory responses, contributes to the overexpression of Shh in pancreatic cancer. In the present study, we found a close positive correlation between NF-KB p65 and Shh expression in surgically resected pancreas specimens, including specimens of chronic pancreatitis and pancreatic adenocarcinoma. We showed that blockade of NF-KB suppressed constitutive expression of Shh mRNA in pancreatic cancer cells. Further activation of NF-KB by inflammatory stimuli, including interleukin-1B, tumor necrosis factor-A, and lipopolysaccharide, induced overexpression of Shh, resulting in activation of the Hh pathway. Overexpression of Shh induced by these stimuli was also suppressed by blockade of NF-KB. NF-KB-induced Shh expression actually activated the Hh pathway in a ligand-dependent manner and enhanced cell proliferation in pancreatic cancer cells. In addition, inhibition of the Hh pathway as well as NF-KB suppressed the enhanced cell proliferation. Our data suggest that NF-KB activation is one of the mechanisms underlying Shh overexpression in pancreatic cancer and that proliferation of pancreatic cancer cells is accelerated by NF-KB activation in part through Shh overexpression.

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“…Although these studies concern the usage of both GLP-1 mimetics and the orally administered gliptins, and our study exclusively focusses on gliptins, and is not concerned with the GLP-1 mimetics data. The close relationship between chronic pancreatitis and pancreatic cancer is also a subject of intense research 45 . Another administrative database study of US adults with type 2 diabetes reported increased odds of hospitalization for acute pancreatitis for patients undergoing GLP-1 based therapies sitagliptin 13 .…”

Section: Discussionmentioning

confidence: 99%

Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins

Chakraborty¹,

Rendón-Ramírez²,

Ásgeirsson³

et al. 2015

F1000Res

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The long term side effects of any newly introduced drug is a subject of intense research, and often raging controversies. One such example is the dipeptidyl peptidase-IV (DPP4) inhibitor used for treating type 2 diabetes, which is inconclusively implicated in increased susceptibility to acute pancreatitis. Previously, based on a computational analysis of the spatial and electrostatic properties of active site residues, we have demonstrated that phosphoinositide-specific phospholipase C (PI-PLC) from Bacillus cereus is a prolyl peptidase using in vivo experiments. In the current work, we first report the inhibition of the native activity of PI-PLC by two DPP4 inhibitors - vildagliptin (LAF-237) and K-579. While vildagliptin inhibited PI-PLC at micromolar concentrations, K-579 was a potent inhibitor even at nanomolar concentrations. Subsequently, we queried a comprehensive, non-redundant set of 5000 human proteins (50% similarity cutoff) with known structures using serine protease (SPASE) motifs derived from trypsin and DPP4. A pancreatic lipase and a gastric lipase are among the proteins that are identified as proteins having promiscuous SPASE scaffolds that could interact with DPP4 inhibitors. The presence of such scaffolds in human lipases is expected since they share the same catalytic mechanism with PI-PLC. However our methodology also detects other proteins, often with a completely different enzymatic mechanism, that have significantly congruent domains with the SPASE motifs. The reported elevated levels of serum lipase, although contested, could be rationalized by inhibition of lipases reported here. In an effort to further our understanding of the spatial and electrostatic basis of DPP4 inhibitors, we have also done a comprehensive analysis of all 76 known DPP4 structures liganded to inhibitors till date. Also, the methodology presented here can be easily adopted for other drugs, and provide the first line of filtering in the identification of pathways that might be inadvertently affected due to promiscuous scaffolds in proteins.

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Chronic pancreatitis, pancreatic adenocarcinoma and the black box in-between

Cited by 74 publications

References 35 publications

Risk Factors for Pancreatic Cancer: Case-Control Study

Risk Factors for Pancreatic Cancer: Case-Control Study

Nuclear Factor-κB Contributes to Hedgehog Signaling Pathway Activation through Sonic Hedgehog Induction in Pancreatic Cancer

Dipeptidyl peptidase-IV inhibitors used in type-2 diabetes inhibit a phospholipase C: a case of promiscuous scaffolds in proteins

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