Cathepsin K: A Versatile Potential Biomarker and Therapeutic Target for Various Cancers

Abstract

Cancer, a common malignant disease, is one of the predominant causes of diseases that lead to death. Additionally, cancer is often detected in advanced stages and cannot be radically cured. Consequently, there is an urgent need for reliable and easily detectable markers to identify and monitor cancer onset and progression as early as possible. Our aim was to systematically review the relevant roles of cathepsin K (CTSK) in various possible cancers in existing studies. CTSK, a well-known key enzyme in the bone resorption process and most studied for its roles in the effective degradation of the bone extracellular matrix, is expressed in various organs. Nowadays, CTSK has been involved in various cancers such as prostate cancer, breast cancer, bone cancer, renal carcinoma, lung cancer and other cancers. In addition, CTSK can promote tumor cells proliferation, invasion and migration, and its mechanism may be related to RANK/RANKL, TGF-β, mTOR and the Wnt/β-catenin signaling pathway. Clinically, some progress has been made with the use of cathepsin K inhibitors in the treatment of certain cancers. This paper reviewed our current understanding of the possible roles of CTSK in various cancers and discussed its potential as a biomarker and/or novel molecular target for various cancers.

Keywords: CTSK; biomarker; cancer; cathepsin K; therapeutic target.

Figure 1

Three-dimensional structure of pro-cathepsin k and cathepsin k. Structures generated on the PDB.

Figure 2

CTSK promotes the invasion and metastasis of prostate cancer, which is related to the receptor activator of NF-κB (RANK) and proinflammatory factors such as interleukin 6 (IL-6).

Figure 3

CTSK can promote the proliferation, invasion and migration of different types of breast cancer cells, especially bone metastasis. There are multiple signaling pathways involved in this process, including RANKL/RANK signaling, NF-κB signal pathways, TGF-β and mTOR signal pathways.

Figure 4

Schematic illustration showing the different mechanisms leading to CTSK expression. Mainly involved in the mTOR signaling pathway, TSC mutations or TFE3 rearrangements or TFEB amplification, which made a vital contribution.

Figure 5

A partial mechanism of action of CTSK in lung cancer. Two pathways of CTSK expression are elucidated: first, transforming growth factor-β (TGF-β) acts as an efficient substrate for CTSK to activate the PI3K and Ras proteins. Second, CTSK is expressed by directly activating the mTOR signaling pathway, mainly the mTORC1 complex.

Figure 6

CTSK is strongly expressed in colorectal cancer, ovarian cancer, gastric cancer and melanoma and promotes the invasion and metastasis of these cancers. Mainly associated with the TLR signaling pathway, CTSK binds to the TLR4 receptor and activates the pathway to function.