Mammalian cysteine protease inhibitors: biochemical properties and possible roles in tumor progression.

The endogenous cysteine protease inhibitors represent the final level at which cysteine protease activity can be regulated. These inhibitors are subdivided into three families (stefins, cystatins and kininogens) which belong to the protein superfamily, cystatins. Cystatins do not form a covalent bond with cysteine proteases, but instead cover the active site cleft blocking access to the active site. The most important biochemical characteristics of the cystatins are described in the first part of this review. Alterations in the balance between endogenous cysteine protease inhibitors and cysteine proteases have been postulated to contribute to malignant progression. A few studies have demonstrated the enrichment of cysteine protease inhibitor activity in the membrane fraction of tumors/cells. Evidence is accumulating that an inverse correlation exists between the level of stefin A, one of the cysteine protease inhibitors, and malignant progression. Stefin A has even been hypothesized to be a tumor suppressor. However, additional studies are necessary in order to prove functional roles for the individual cysteine protease inhibitors in tumor growth and progression.