Polycystins in Colorectal Cancer

Abstract

Cell and extracellular matrix (ECM) biomechanics emerge as a distinct feature during the development and progression of colorectal cancer (CRC). Polycystins are core mechanosensitive protein molecules that mediate mechanotransduction in a variety of epithelial cells. Polycystin-1 (PC1) and polycystin-2 (PC2) are engaged in signal transduction mechanisms and during alterations in calcium influx, which regulate cellular functions such as proliferation, differentiation, orientation, and migration in cancer cells. Recent findings implicate polycystins in the deregulation of such functions and the formation of CRC invasive phenotypes. Polycystins participate in all aspects of the cell's biomechanical network, from the perception of extracellular mechanical cues to focal adhesion protein and nuclear transcriptional complexes. Therefore, polycystins could be employed as novel biomarkers and putative targets of selective treatment in CRC.

Keywords: colorectal cancer; mechanobiology; mechanotransduction; polycystins; prognostic biomarkers.

Figure 1

Molecular structure of polycystins. Polycystin-1 has a long N-terminal end with 16 copies of the polycystic kidney disease (PKD) domain and additional domains for cell-to-cell and cell-to-matrix interactions. It has eleven transmembrane domains and a C-terminus that interacts with the Polycystin-2 C-terminus, therefore functioning as a protein complex. Polycystin-2 has six transmembrane domains and both ends are intracellular or in the interior of cell organelles, such as the endoplasmic reticulum. PC1, polycystin-1; PC2, polycystin-2 (Reprinted from Reference [8], © 2015, with permission from Elsevier).

Figure 2

Proposed mechanisms of polycystins implication in CRC. PC1 senses extracellular mechanical cues and regulates cell-to-cell and cell-to-ECM interactions in order to potentially increase matrix rigidity. PC2 mediates alterations in calcium influx and activates the mTOR signaling pathway. PC1 may also mediate cancer cell properties through β-catenin (Wnt pathway) and interacts with focal adhesion molecules (FAK, Src) and RTKs. Finally, PC1 regulates the activity of downstream transcription factors (AP-1, NF-κB, TAZ) through the PC1-CTT. CRC, colorectal cancer; 4EBP1, 4E binding protein 1; AP-1, activator protein-1; CTT, C-terminal intracellular tail; ECM, extracellular matrix; FAK, focal adhesion kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-kappaB; PC1, polycystin-1; PC2, polycystin-2; p70S6K, p70S6 kinase; RTK, receptor tyrosine kinase; TAZ, transcriptional coactivator with PDZ-binding motif