Cathepsin L inactivation leads to multimodal inhibition of prostate cancer cell dissemination in a preclinical bone metastasis model

Abstract

It is estimated that approximately 90% of patients with advanced prostate cancer develop bone metastases; an occurrence that results in a substantial reduction in the quality of life and a drastic worsening of prognosis. The development of novel therapeutic strategies that impair the metastatic process and associated skeletal adversities is therefore critical to improving prostate cancer patient survival. Recognition of the importance of Cathepsin L (CTSL) to metastatic dissemination of cancer cells has led to the development of several CTSL inhibition strategies. The present investigation employed intra-cardiac injection of human PC-3ML prostate cancer cells into nude mice to examine tumor cell dissemination in a preclinical bone metastasis model. CTSL knockdown confirmed the validity of targeting this protease and subsequent intervention studies with the small molecule CTSL inhibitor KGP94 resulted in a significant reduction in metastatic tumor burden in the bone and an improvement in overall survival. CTSL inhibition by KGP94 also led to a significant impairment of tumor initiated angiogenesis. Furthermore, KGP94 treatment decreased osteoclast formation and bone resorptive function, thus, perturbing the reciprocal interactions between tumor cells and osteoclasts within the bone microenvironment which typically result in bone loss and aggressive growth of metastases. These functional effects were accompanied by a significant downregulation of NFκB signaling activity and expression of osteoclastogenesis related NFκB target genes. Collectively, these data indicate that the CTSL inhibitor KGP94 has the potential to alleviate metastatic disease progression and associated skeletal morbidities and hence may have utility in the treatment of advanced prostate cancer patients.

Presurgical weight loss affects tumour traits and circulating biomarkers in men with prostate cancer

“…Similar to most weight loss trials, we also detected a solid correlation between the rate of weight loss and the loss of lean mass, although it is interesting to see that weight loss invokes similar catabolic gene expression profiles within the prostatic tumour, as observed in heart or skeletal muscle. Upregulation of CTSL is of concern because of its association with increased osteoclast formation, bone resorption, bone loss, and metastatic potential ( Sudhan et al , 2016 ). Given that the intervention was effective in reducing caloric intake, but not as effective in increasing PA, it is speculated that perhaps the losses in lean mass could have been mitigated and the upregulation of CTSL diminished if we had been able to activate men in the WLI arm, and include both aerobic and resistance PA.…”

Cathepsin L in tumor angiogenesis and its therapeutic intervention by the small molecule inhibitor KGP94

“…Conversely, tumor progression studies in CTSL −/− mice revealed that CTSL deficiency significantly hampered the progression of benign encapsulated pancreatic tumors into highly invasive carcinomas [21]. Further, our previous findings have reported that pharmacological inhibition of CTSL using 3-bromophenyl-3-hydroxyphenyl-ketone thiosemicarbazone (KGP94) significantly impairs the invasive and metastatic capacities of human breast and prostate cancer cells [22–24]. While these studies are clearly indicative of the importance of CTSL in metastatic progression, they shed little light on the involvement of CTSL in the angiogenic process.…”

Overexpression of Cathepsin L is associated with chemoresistance and invasion of epithelial ovarian cancer

“…CTSL, a lysosomal endopeptidase expressed in most eukaryotic cells, is a member of the papain-like family of cysteine proteinases, which is reported to be associated with cancer tumorigenesis, proliferation and migration [14]. CTSL has been proven to be upregulated in a variety of malignancies, and the level of CTSL expression is associated with the degree of malignancy [15–16]. …”