Two members of the TRiC chaperonin complex, CCT2 and TCP1 are essential for survival of breast cancer cells and are linked to driving oncogenes

Guest, Stephen T.; Kratche, Zachary; Bollig‐Fischer, Aliccia; Haddad, Ramsi; Ethier, Stephen P.

doi:10.1016/j.yexcr.2015.02.005

Cited by 95 publications

(97 citation statements)

References 47 publications

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“…CCT inhibition results in the changes in cytoskeletal dynamics and inhibition of actin and tubulin polymerization that we observed in CT20p-treated cells 21-22. Our studies and that of others have reported that CCT is overexpressed in cancer cells and could be an indicator of cancer progression and metastasis 23-26, which makes it a novel target for cancer therapeutics. Interestingly, the cytotoxicity of CT20p in breast cancer cells correlated with the levels of CCT, which was decreased by comparison in normal breast epithelial cells 22.…”

Section: Introductionsupporting

confidence: 68%

PSMA-Targeted Theranostic Nanocarrier for Prostate Cancer

et al. 2017

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Herein, we report the use of a theranostic nanocarrier (Folate-HBPE(CT20p)) to deliver a therapeutic peptide to prostate cancer tumors that express PSMA (folate hydrolase 1). The therapeutic peptide (CT20p) targets and inhibits the chaperonin-containing TCP-1 (CCT) protein-folding complex, is selectively cytotoxic to cancer cells, and is non-toxic to normal tissue. With the delivery of CT20p to prostate cancer cells via PSMA, a dual level of cancer specificity is achieved: (1) selective targeting to PSMA-expressing prostate tumors, and (2) specific cytotoxicity to cancer cells with minimal toxicity to normal cells. The PSMA-targeting theranostic nanocarrier can image PSMA-expressing cells and tumors when a near infrared dye is used as cargo. Meanwhile, it can be used to treat PSMA-expressing tumors when a therapeutic, such as the CT20p peptide, is encapsulated within the nanocarrier. Even when these PSMA-targeting nanocarriers are taken up by macrophages, minimal cell death is observed in these cells, in contrast with doxorubicin-based therapeutics that result in significant macrophage death. Incubation of PSMA-expressing prostate cancer cells with the Folate-HBPE(CT20p) nanocarriers induces considerable changes in cell morphology, reduction in the levels of integrin β1, and lower cell adhesion, eventually resulting in cell death. These results are relevant as integrin β1 plays a key role in prostate cancer invasion and metastatic potential. In addition, the use of the developed PSMA-targeting nanocarrier facilitates the selective in vivo delivery of CT20p to PSMA-positive tumor, inducing significant reduction in tumor size.

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Section: Introductionsupporting

confidence: 68%

PSMA-Targeted Theranostic Nanocarrier for Prostate Cancer

et al. 2017

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“…Examining the results of the two-drug combination treatments revealed that combining Navitoclax with either the FGFR or the PI3′kinase inhibitor reduced colony-forming ability by approximately 50-fold. The similarity of the results for the FGFR and PI3′K inhibitors in combination with the BCL2L1 inhibitor is in agreement with our recently published results showing that in SUM-185 cells, FGFR3 and PIK3CA both function to drive AKT phosphorylation [44]. These results suggest that, in the context of a functional oncogene signature, targeting a driver oncogene that mediates AKT phosphorylation in combination with targeting BCL2L1 has synergistic effects on cell viability even when the drugs are used at low doses.…”

Section: Resultssupporting

confidence: 90%

“…In a previous study, we demonstrated that amplified FGFR2 and mutant PIK3CA were linked to AKT phosphorylation in SUM-185 cells, and that targeting either oncogene alone induced potent inhibition of cell proliferation. However, this growth inhibition was reversible as indicated by small decreases in clonogenic capacity following drug removal [44]. By contrast, simultaneous inhibition of FGFR2 and BCL2L1, or PIK3CA and BCL2L1 in SUM-185 cells resulted in dramatic reductions in clonogenic survival.…”

Section: Discussionmentioning

confidence: 99%

Functional oncogene signatures guide rationally designed combination therapies to synergistically induce breast cancer cell death

et al. 2016

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A critical first step in the personalized approach to cancer treatment is the identification of activated oncogenes that drive each tumor. The Identification of driver oncogenes on a patient-by-patient basis is complicated by the complexity of the cancer genome and the fact that a particular genetic alteration may serve as a driver event only in a subset of tumors that harbor it. In this study, we set out to identify the complete set of functional oncogenes in a small panel of breast cancer cell lines. The cell lines in this panel were chosen because they each contain a known receptor tyrosine kinase (RTK) oncogene. To identify additional drivers, we integrated functional genetic screens with copy number and mutation analysis, and cancer genome knowledge databases. The resulting functional oncogene signatures were able to predict responsiveness of cell lines to targeted inhibitors. However, as single agents, these drugs had little effect on clonogenic potential. By contrast, treatment with drug combinations that targeted multiple oncogenes in the signatures, even at very low doses, resulted in the induction of apoptosis and striking synergistic effects on clonogenicity. In particular, targeting a driver oncogene that mediates AKT phosphorylation in combination with targeting the anti-apoptotic BCL2L1 protein had profound effects on cell viability. Importantly, because the synergistic induction of cell death was achieved using low levels of each individual drug, it suggests that a therapeutic strategy based on this approach could avoid the toxicities that have been associated with the combined use of multiple-targeted agents.

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“…A recent study reported that CCT contributed to the metastasis of breast cancer to bone by folding AIB1 (36). Another determined that the genes for CCTα and CCTβ were amplified in breast cancer and necessary for cancer growth and proliferation (37). In hepatocellular carcinomas, the CCTζ subunit acted in an oncogenic manner, correlating with increased cancer severity and poor prognosis (38).…”

Section: Discussionmentioning

confidence: 99%

Chaperonin Containing TCP-1 Protein Level in Breast Cancer Cells Predicts Therapeutic Application of a Cytotoxic Peptide

Bassiouni

Nemec

Iketani

et al. 2016

Clinical Cancer Research

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Purpose: Metastatic disease is a leading cause of death for patients with breast cancer, driving the need for new therapies. CT20p is a peptide previously discovered by our group that displays cancer-specific cytotoxicity. To design the optimal therapeutic use of the peptide, we identified the intracellular target of CT20p in breast cancer cells, correlating expression patterns of the target with susceptibility to CT20p. Experimental Design: Using polymeric nanoparticles to deliver CT20p, we assessed cytoskeletal changes, cell migration, adhesion, and viability in cells treated with the peptide. Protein pull-down experiments, coupled to mass spectrometry, enabled identification of the peptide's intracellular target. Biochemical and histologic techniques validated target identity in human cell lines and breast cancer tissue microarrays and revealed susceptibility patterns to CT20p. Results: Chaperonin containing TCP-1 (CCT) was identified as the intracellular target of CT20p. Cancer cells susceptible to CT20p had increased CCT, and overexpression of CCTβ, a subunit of the CCT complex, enhanced susceptibility to CT20p. Susceptible cells displayed reduced tubulin, a substrate of CCT, and inhibition of migration upon CT20p treatment. CCTβ levels were higher in invasive ductal carcinomas than in cancer adjacent tissues and increased with breast cancer stage. Decreased breast cancer patient survival correlated with genomic alternations in CCTβ and higher levels of the chaperone. Conclusions: Increased CCT protein in breast cancer cells underlies the cytotoxicity of CT20p. CCT is thus a potential target for therapeutic intervention and serves as a companion diagnostic to personalize the therapeutic use of CT20p for breast cancer treatment. Clin Cancer Res; 22(17); 4366–79. ©2016 AACR.

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Two members of the TRiC chaperonin complex, CCT2 and TCP1 are essential for survival of breast cancer cells and are linked to driving oncogenes

Cited by 95 publications

References 47 publications

PSMA-Targeted Theranostic Nanocarrier for Prostate Cancer

PSMA-Targeted Theranostic Nanocarrier for Prostate Cancer

Functional oncogene signatures guide rationally designed combination therapies to synergistically induce breast cancer cell death

Chaperonin Containing TCP-1 Protein Level in Breast Cancer Cells Predicts Therapeutic Application of a Cytotoxic Peptide

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