Lefty peptides, derived by MMP2 cleavage, act as a new class of gelatinase A inhibitor.

MMPs are zinc-dependent endopeptidases that are involved in proteolysis of extracellular matrix in both physiological and pathological processes including cancer. MMPs are involved at all stages of tumor progression, including tumor growth, angiogenesis, and metastasis. We recently showed that overexpression of Lefty in cancer cells restrains tumor growth. Here, we show that small forms of Lefty are generated by MMP2 (gelatinase A) mediated cleavage. In turn, these forms of Lefty strongly inhibit the autocatalytic, gelatinolytic and caseinolytic activities of MMP2 in vitro. We show that a short synthesized form of Lefty peptide (CASDGALVP) inhibits gelatinolytic and caseinolytic activities of MMP2 in vitro and inhibits tumor growth in vivo. Together, these findings show that lefty peptides are a new class of gelatinase A inhibitors that restrain tumor growth.