SPINK1: A New Therapeutic Target in Cancer?

Abstract

The serine protease inhibitor Kazal type 1 (SPINK1)2 was initially isolated from bovine pancreas by Kazal and colleagues. A similar protease inhibitor was later identified in human pancreatic juice and called “pancreatic secretory trypsin inhibitor.” By means of immunologic techniques, SPINK1 was later identified as a tumor-associated peptide and isolated from the urine of a patient with ovarian cancer. Hence, it was called “tumor-associated trypsin inhibitor” (TATI) (1). This name has been used in most studies of its use as a tumor marker [reviewed in (2)]. TATI was shown to be a serum and urine marker for many types of cancer, but it was not found to be superior to earlier known markers that had been identified for diagnostic use. It was an independent prognostic marker for several types of cancer, however. Tumors producing SPINK1 have been shown to also produce trypsin, and because trypsin activates matrix metalloproteinases, which have been shown to mediate cancer invasion, an association between SPINK1 production and an adverse prognosis in cancer was ascribed to its coproduction with trypsin. SPINK1 was thought to have a role in cancer similar to the one it has in the pancreas, where it protects the pancreas by inhibiting prematurely activated trypsin (2). Mechanisms by which SPINK1 could exert alternative functions were suggested by its structural similarities with epidermal growth factor (EGF): a 50% sequence homology, a molecular size of approximately 6 kDa, and the presence of 3 intrachain disulfide bridges (2). This similarity with EGF prompted studies on the ability of SPINK1 to act as a growth factor. In 1985, SPINK1 was shown to bind to surface receptors and to stimulate DNA synthesis in …