Targeting chaperonin containing TCP1 (CCT) as a molecular therapeutic for small cell lung cancer

Abstract

Identifying new druggable targets is desired to meet the needs for effective cancer treatments. To this end, we previously reported the efficacy of a therapeutic peptide called CT20p that displays selective cytotoxicity through inhibition of a multi-subunit, protein-folding complex called Chaperonin-Containing TCP-1 (CCT). To investigate the role of CCT in cancer progression, we examined protein levels of CCT subunits in liver, prostate, and lung cancer using human tissue microarrays. We found that these cancers expressed higher levels of CCT2 as compared to normal tissues. Small cell lung cancer (SCLC) stood out as having statistically significant difference in CCT2. Higher levels of CCT2 in tumors from lung cancer patients were also associated with decreased survival. Using SCLC cell lines, we observed detectable amounts of CCT subunits and cells were susceptible to killing by CT20p. Treatment with CT20p, delivered to cells using polymeric nanoparticles, was cytotoxic to all SCLC cell lines, decreasing the levels of CCT client proteins like STAT3. In contrast, treatment with a STAT3 inhibitor was effective in one of the SCLC cell lines. While we found that CCT levels could vary in cell lines, normal tissues had low levels of CCT and minimal toxicity to liver or kidney function was observed in mice treated with CT20p. These results indicate that in SCLC, changes in CCT levels could be used as a biomarker for diagnosis and that targeting CCT for inhibition with CT20p is a promising treatment approach for those cancers such as SCLC that currently lack targeted therapeutics.

Investigating Chaperonin-Containing TCP-1 subunit 2 as an essential component of the chaperonin complex for tumorigenesis

“…The goal of this study is to determine whether the contribution of CCT chaperonin complex to carcinogenesis can be elucidated by focusing on a single subunit, CCT2. We and others showed that CCT2 is increased in breast, prostate, and lung cancer as compared to normal tissues and that CT20p directly interacts with CCT2 [14][15][16]21 . But whether CCT2 is an essential component of the chaperonin's activity in cancer cells and promotes tumorigenesis is unknown.…”

“…another class of protein-folding complexes, called chaperonins, gained interest with the recognition that cancer cells highly express these mediators of protein-folding [14][15][16][17][18][19][20][21][22][23] . The cytosolic, eukaryotic chaperonin-containing TCP-1 (CCT) is an emerging player in neoplastic transformation with potential for development as a novel diagnostic marker and therapeutic target.…”

“…Previous reports estimated that in eukaryotic cells, CCT facilitates the folding of approximately 10% of newly synthesized proteins, co-and post-translationally [27][28][29] , with actin and tubulin being obligate substrates 30 . In cancer cells, CCT could potentially fold more proteins, with substrates including oncogenic proteins and mediators such as KRAS, STAT3, among others 14,20,[31][32][33] . Genomic amplification of CCT or upregulation of gene expression suggests that CCT could be a marker for oncogenesis 34 .…”

“…Genomic amplification of CCT or upregulation of gene expression suggests that CCT could be a marker for oncogenesis 34 . Previous studies reported that the expression levels of different CCT subunits are upregulated in various cancers, such as CCT8 and CCT3 in hepatocellular carcinoma 18,22 or glioblastoma 35 , and CCT2 in prostate, breast, and lung cancers 14,15,21 . Our lab discovered a CCT inhibitor called CT20p that kills cancer cells in a CCT-dependent manner.…”

“…Our lab discovered a CCT inhibitor called CT20p that kills cancer cells in a CCT-dependent manner. Cancer cells in which CCT was inhibited were resistant to CT20p killing, while cells in which CCT was increased were susceptible 14,16 . However, the complexity of CCT, with its multiple subunits, and the lack of a full understanding of CCT substrate selectivity in vivo, are some of the challenge that hinder the development of promising therapeutics like CT20p.…”