Abstract
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 in vitro and in vivo. 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.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/21/5536/F1.large.jpg.
Highlights
High-grade serous ovarian carcinoma (HGSOC) is the most common and most aggressive type of ovarian cancer [1]
Increasing chromosomal instability (CIN) is cytotoxic to ovarian cancer cells We investigated the consequences of increasing CIN in ovarian cancer cells, including two HGSOC cell lines (TOV1946 and TOV2223), and three cell lines likely derived from nonserous ovarian tumors (SKOV3, TOV21G, and A2780; refs. 28, 29)
It is thought that mutation in TP53 is an early event in the pathogenesis of HGSOC, as abnormal nuclear localization of p53 protein is observed in the precursor lesion, serous tubal intraepithelial carcinoma, and in adjacent morphologically normal FTSECs [38]
Summary
High-grade serous ovarian carcinoma (HGSOC) is the most common and most aggressive type of ovarian cancer [1]. Largescale sequencing efforts, including The Cancer Genome Atlas 2), have revealed a complex genomic landscape, dominated by gene copy-number alterations, as well as gains and losses of chromosome arms or entire chromosomes. Considered to be a driving force in the development and progression of cancer, chromosomal instability (CIN), when occurring in normal cells, can compromise cellular viability and proliferation [4,5,6,7,8,9]. The added burden on the protein degradation machinery renders aneuploid cells prone to aggregation of misfolded proteins [6, 7, 9, 10]. Chromosome missegregation causes endoplasmic reticulum (ER) stress, with expansion of the ER and activation of the unfolded protein response Chromosome missegregation causes endoplasmic reticulum (ER) stress, with expansion of the ER and activation of the unfolded protein response (UPR; refs. 4, 11)
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