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Cleavage of ß-Catenin by Calpain in Prostate and Mammary Tumor Cells

¹ Cellular and Molecular Biology Graduate Program, ² Department of Urology, ³ Michigan Urology Center, ⁴ Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan; and the ⁵ Department of Urology, University of Ulm, Ulm, Germany

Mutations in the NH₂-terminal regulatory domain of the ß-catenin gene lead to aberrant stabilization and accumulation of the protein and increased TCF/LEF-dependent transcription. Although these mutations are common in some cancers, they are infrequent in prostate and breast cancer. We have found that metastatic prostate cancer specimens, obtained through a rapid autopsy tissue procurement program, expressed a novel M_r 75,000 proteolytic fragment of ß-catenin (ß-cat⁷⁵). ß-Cat⁷⁵ was also expressed in multiple prostate and breast cancer cell lines and was closely associated with the activity of the calcium-dependent protease, calpain. In a prostate cancer cDNA microarray, m-calpain RNA levels were found to be significantly increased in metastatic disease compared with normal prostate. We showed calpain-dependent generation of ß-cat⁷⁵ in cell culture and in vitro. Molecular mapping revealed that calpain cleavage removed the NH₂-terminal regulatory domain of the ß-catenin protein. Treatment of MCF-7 cells with ionomycin led to increased accumulation of ß-cat⁷⁵ in the nucleus and TCF-dependent transcriptional activity. Overexpression of a similar ß-catenin fragment that lacks the NH₂-terminal 132 amino acids and has transforming potential activated TCF-dependent transcription. Given the low frequency of mutation-induced activation of ß-catenin in prostate and breast cancers, proteolytic cleavage of ß-catenin by calpain may represent a novel mechanism by which the protein is activated during tumorigenesis.

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