SPINK1 Pancreatic Cancer Pathway

Serine protease inhibitor, Kazal type 1 (SPINK1), also known as pancreatic secretory trypsin inhibitor (PSTI) and tumor-associated trypsin inhibitor (TATI), is mainly produced in the acinar cells of the exocrine pancreas, but also is expressed by mucus-secreting cells throughout the gastrointestinal tract and in the kidney, lung and breast. The main physiological role of SPINK1 is to serve as a first line inhibitor of trypsin in the event of premature trypsinogen activation. It is capable of inhibiting around 20% of the total activity of trypsin in the acinar cells and the pancreatic ducts. SPINK1 is an efficient inhibitor of trypsin-1 and trypsin-2, but not of trypsin-3.Acute pancreatitis can be caused by inappropriate conversion of trypsinogen to trypsin within the pancreatic acinar cells, leading to tissue damage and inflammation, including activation of protease-activated receptors like PAR2/F2RL1. This altered microenvironment, affecting and activating acinar, ductal, and stellate cells, promotes fibrosis and cancer development. Many mutations in SPINK1 have been discovered in familial pancreatitis, including the high-risk N34S haplotype, which is associated with chronic pancreatitis, a risk factor for pancreatic ductal adenocarcinoma.Apart from its normal expression in pancreatic cells and the GI tract, severe infections and tissue destruction cause elevation of SPINK1 in serum and urine, suggesting that it is an acute phase protein of the immune system. SPINK1 is overexpressed in various human cancers including the pancreas, colon, lung, breast and prostate. Increased serum SPINK1 level has been correlated with aggressive cancer disease and poor prognosis, but its role, whether secondary to inflammation and protease expression, or causal, remains uncertain.