Chromosomal Instability and mTORC1 Activation through PTEN Loss Contribute to Proteotoxic Stress in Ovarian Carcinoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2019-11, Vol.79 (21), p.5536-5549
• Main Authors: Chui, M Herman, Doodnauth, Sasha A, Erdmann, Natalie, Tiedemann, Rodger E, Sircoulomb, Fabrice, Drapkin, Ronny, Shaw, Patricia, Rottapel, Robert
• Format: Article
• Language: English
• Subjects: Animals; Bortezomib - pharmacology; Carcinoma, Ovarian Epithelial - drug therapy; Carcinoma, Ovarian Epithelial - genetics; Carcinoma, Ovarian Epithelial - pathology; Cell Line, Tumor; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Chromosomal Instability - drug effects; Chromosomal Instability - genetics; Cystadenocarcinoma, Serous - drug therapy; Cystadenocarcinoma, Serous - genetics; Cystadenocarcinoma, Serous - pathology; Epithelium - drug effects; Epithelium - pathology; Fallopian Tube Neoplasms - genetics; Fallopian Tube Neoplasms - pathology; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Humans; Mechanistic Target of Rapamycin Complex 1 - genetics; Mice; Mice, Inbred NOD; Mice, SCID; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors - pharmacology; PTEN Phosphohydrolase - genetics; Signal Transduction - drug effects; Signal Transduction - genetics; Unfolded Protein Response - drug effects; Unfolded Protein Response - genetics
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-18-3029

High-grade serous ovarian carcinoma commonly arises from fallopian tube secretory epithelium and is characterized by a high level of chromosomal instability. To model the acquisition of aneuploidy during early carcinogenesis, chromosome missegregation was induced in immortalized tubal epithelial cells, which proved acutely detrimental to cellular fitness. The phenotype was characterized by accumulation of misfolded proteins, activation of the unfolded protein response (UPR), decreased protein synthesis, and enhanced vulnerability to proteasome inhibition. However, chromosome missegregation also resulted in heightened transformation potential, assessed by colony formation in soft agar. Ovarian cancer cells retained intrinsic sensitivity to proteasome inhibitors under adherent culture conditions, but acquired resistance as spheroids (recapitulating their native configuration in ascites) by downregulating protein synthesis via mTORC1 suppression. Loss of PTEN drove constitutive mTORC1 activity, enhanced proteotoxic stress, as evidenced by UPR induction, and resensitized tumor spheroids to proteasome inhibition both and . In cohorts of primary ovarian carcinomas, mTORC1 and UPR signaling pathways were closely associated. These results implicate attenuation of protein synthesis as a protective mechanism in tumor spheroids, which may explain the overall poor response to bortezomib in clinical trials of patients with advanced ovarian cancer. However, patients with PTEN-deficient tumors may represent a subpopulation potentially amenable to treatment with proteasome inhibitors or other therapeutic agents that disrupt protein homeostasis. SIGNIFICANCE: Chromosome instability and protein synthesis are important factors that determine the efficacy of proteotoxic stress-inducing agents, such as proteasome inhibitors, in the treatment of ovarian cancer. http://cancerres.aacrjournals.org/content/canres/79/21/5536/F1.large.jpg.