SPINK1 General 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 is also 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 of defense against 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 is an autodigestive disorder, in which inappropriate conversion of trypsinogen to trypsin within the pancreatic acinar cells leads to the development of pancreatitis. 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, severe infections and tissue destruction cause elevation of SPINK1 in serum and urine, suggesting that this protein also acts as an acute phase protein. SPINK1 is overexpressed in various human cancers including those of the pancreas, colon, lung, breast and prostate. Increased serum SPINK1 level has been correlated with aggressive cancer disease and poor prognosis. SPINK1 may mediate tumor growth and metastasis via stimulation of the EGF-receptor, to which it binds, at slightly lower affinity than EGF. Since its expression is raised by inflammatory conditions, which is common in cancer settings, it may act through autocrine and paracrine signaling. Overexpression of SPINK1 in cancer may also, via inhibition of key proteases, block cancer cell apoptosis resulting in suppression of the immune response and escape of cancer cells from immune surveillance.