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

// Ana C. Carr 1 , Amr S. Khaled 2 , Rania Bassiouni 1 , Orielyz Flores 1 , Daniel Nierenberg 1 , Hammad Bhatti 2 , Priya Vishnubhotla 2 , J. Manuel Perez 3 , Santimukul Santra 4 and Annette R. Khaled 1 1 Burnett School of Biomedical Science, College of Medicine, University of Central Florida, Orlando, FL 32827, USA 2 Department of Pathology and Laboratory Medicine, Department of Internal Medicine, Orlando VA Medical Center, Orlando, FL 32803, USA 3 Biomedical Imaging Research Institute, & Samuel Oschin Comprehensive Cancer Institute, Department of Biomedical Sciences and Department of Neurosurgery, Cedar Sinai Medical Center, Los Angeles, CA 90048, USA 4 Department of Chemistry, Pittsburg State University, Pittsburg, KS 66762, USA Correspondence to: Annette R. Khaled, email: annette.khaled@ucf.edu Keywords: chaperone; lung cancer; peptide; STAT3; nanoparticles Received: August 16, 2017      Accepted: November 05, 2017      Published: November 25, 2017 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.