Tat-hspb1 Suppresses Clear Cell Renal Cell Carcinoma (ccRCC) Growth via Lysosomal Membrane Permeabilization

Simple Summary In this study, we discovered a novel endogenous peptide derived from HSPB1 protein through peptidomic analysis of human renal clear cell carcinoma and adjacent normal tissues. We generated a new peptide by conjugating this HSPB1-derived peptide with the HIV-Tat, named Tat-hspb1. We found that Tat-hspb1 could inhibit the proliferation and migration of ccRCC cells. Furthermore, Tat-hspb1 could induce lysosomal membrane permeabilization (LMP) and apoptosis of ccRCC cells while being less cytotoxic to normal epithelial cells. Tat-hspb1 may be a potential therapeutic agent for renal cancer. Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer, of which the incidence is increasing worldwide with a high mortality rate. Bioactive peptides are considered a significant class of natural medicines. We applied mass spectrometry-based peptidomic analysis to explore the peptide profile of human renal clear cell carcinoma and adjacent normal tissues. A total of 18,031 peptides were identified, of which 105 unique peptides were differentially expressed (44 were up-regulated and 61 were down-regulated in ccRCC tissues). Through bioinformatic analysis, we finally selected one peptide derived from the HSPB1 protein (amino acids 12-35 of the N-terminal region of HSPB1). Next, we fused this peptide to the HIV-Tat, generated a novel peptide named Tat-hspb1, and found that Tat-hspb1 inhibited ccRCC cells' viability while being less cytotoxic to normal epithelial cells. Furthermore, Tat-hspb1 induced apoptosis and inhibited the proliferation and migration of ccRCC cells. Furthermore, we demonstrated that Tat-hspb1 was predominantly localized in lysosomes after entering the ccRCC cell and induced lysosomal membrane permeabilization (LMP) and the release of cathepsin D from lysosomes. Taken together, Tat-hspb1 has the potential to serve as a new anticancer drug candidate.

Automated summary

A novel endogenous peptide derived from HSPB1 protein, Tat-hspb1, was discovered to inhibit the proliferation and migration of ccRCC cells with lower cytotoxicity to normal cells, suggesting its potential as a therapeutic agent for renal cancer.