p53 protein aggregation promotes platinum resistance in ovarian cancer

Abstract

High-grade serous ovarian carcinoma (HGSOC), the most lethal gynecological cancer, often leads to chemoresistant diseases. The p53 protein is a key transcriptional factor regulating cellular homeostasis. A majority of HGSOCs have inactive p53 because of genetic mutations. However, genetic mutation is not the only cause of p53 inactivation. The aggregation of p53 protein has been discovered in different types of cancers and may be responsible for impairing the normal transcriptional activation and pro-apoptotic functions of p53. We demonstrated that in a unique population of HGSOC cancer cells with cancer stem cell properties, p53 protein aggregation is associated with p53 inactivation and platinum resistance. When these cancer stem cells differentiated into their chemosensitive progeny, they lost tumor-initiating capacity and p53 aggregates. In addition to the association of p53 aggregation and chemoresistance in HGSOC cells, we further demonstrated that the overexpression of a p53-positive regulator, p14ARF, inhibited MDM2-mediated p53 degradation and led to the imbalance of p53 turnover that promoted the formation of p53 aggregates. With in vitro and in vivo models, we demonstrated that the inhibition of p14ARF could suppress p53 aggregation and sensitize cancer cells to platinum treatment. Moreover, by two-dimensional gel electrophoresis and mass spectrometry we discovered that the aggregated p53 may function uniquely by interacting with proteins that are critical for cancer cell survival and tumor progression. Our findings help us understand the poor chemoresponse of a subset of HGSOC patients and suggest p53 aggregation as a new marker for chemoresistance. Our findings also suggest that inhibiting p53 aggregation can reactivate p53 pro-apoptotic function. Therefore, p53 aggregation is a potential therapeutic target for reversing chemoresistance. This is paramount for improving ovarian cancer patients' responses to chemotherapy, and thus increasing their survival rate.

Aggregation and Prion-Like Properties of Misfolded Tumor Suppressors: Is Cancer a Prion Disease?

“…These cells lost the capacity for p53 aggregation and tumor development when they differentiated into chemosensitive progenies. Because p53 aggregation was dependent on the overexpression of p14ARF in the stem cell lines, its inhibition resulted in suppression of p53 aggregation (Yang-Hartwich et al 2015). It seems that WT p53 behaves as a mutant conformation in stem cells of HGSOC.…”

“…Using a different strategy, Yang-Hartwich et al (2015) found that WT p53 in stem cells of HGSOC also had the property to aggregate. These cells lost the capacity for p53 aggregation and tumor development when they differentiated into chemosensitive progenies.…”

“…Furthermore, a high level of p53 immunostaining was observed within aggregates containing mutant and WT p53 in prostate cancer samples (Kluth et al 2014). Finally, it was shown that in a population of high-grade serous ovarian carcinoma (HGSOC) cancer cells exhibiting cancer stem cell properties, p53 aggregation is associated with p53 LoF and platinum resistance; however, when HGSOC cells differentiated into their chemosensitive progeny, they lost their capacity for both tumor initiation and p53 aggregation (Yang-Hartwich et al 2015). Furthermore, the overexpression of p14ARF, a positive regulator of p53, inhibited MDM2-mediated p53 degradation and led to an imbalance in p53 turnover that promoted the formation of p53 aggregates.…”

“…When p14ARF was inhibited, p53 aggregation was suppressed, and the cancer cells became sensitized to platinum treatment. Moreover, using two-dimensional gel electrophoresis and mass spectrometry, Yang-Hartwich et al (2015) discovered that aggregated p53 acts uniquely by interacting with proteins involved in cancer cell survival and tumor progression. This correlation between p53 aggregation and platinum resistance is relevant to the poor prognosis of patients with HGSOC (Yang-Hartwich et al 2015).…”

Meeting Report From the 2016 11th Biennial Ovarian Cancer Research Symposium

“…Building up on their previous work on the role of p53 aggregation in p53 inactivation and platinum resistance, 17 Yang Yang-Harwitch, PhD (Yale University), Gil Mor, MD, and colleagues presented their recent work on the relationship between transcription factor Twist1 and p53 in mediating EMT and metastasis (manuscript not published). Twist1 has been associated with EMT promotion, enhanced migration, and CSC status.…”