Targeting Cathepsin B for Cancer Therapies

Cathepsin B is a member of the papain family of cysteine proteases normally present in the lysosome, but it can translocate and function to degrade components of the extracellular matrix. It exhibits carboxyopeptidase, peptidyldipepidase, and endopeptidase activity. Aberrant overexpression of cathepsin B has been reported in invasive and metastatic cancers, including breast cancer, melanoma and colorectal cancer. It has been shown that oncogenic activation, such as the signaling of the ErbB pathways, can lead to cathepsin B overexpression. The degradation of the extracellular matrix is a key factor for cathepsin B to contribute to development and metastasis of tumors. An example of substrates for cathepsin B is E-cadherin, which is involved in adherens junctions, and the downregulation of E-cadherin in cancer is directly linked to invasion and metastasis. Recent studies also point to a role for cathepsin B in macrophages in the tumor microenvironment. The structure of cathepsin B is crystallographically solved, and several highly selective and potent inhibitors for cathepsin B have been developed. Yet it remains to be a challenge to demonstrate the clinical utility or benefit of any cathepsin B inhibitor. As cathepsin B is required for a cellular process called lysosomal membrane permeabilization (LMP), inhibition of cathepsin B would protect cancer cells from cell death induced by chemotherapeutic agents. It is expected that combining cathepsin B inhibitors with other approaches, such as nanoparticles, to direct the inhibition to the extracellular space may lead to better clinical approaches to treat cancers and metastasis.