Oncogenic Gain of Function in Glioblastoma Is Linked to Mutant p53 Amyloid Oligomers

Abstract

Tumor-associated p53 mutations endow cells with malignant phenotypes, including chemoresistance. Amyloid-like oligomers of mutant p53 transform this tumor suppressor into an oncogene. However, the composition and distribution of mutant p53 oligomers are unknown and the mechanism involved in the conversion is sparse. Here, we report accumulation of a p53 mutant within amyloid-like p53 oligomers in glioblastoma-derived cells presenting a chemoresistant gain-of-function phenotype. Statistical analysis from fluorescence fluctuation spectroscopy, pressure-induced measurements, and thioflavin T kinetics demonstrates the distribution of oligomers larger than the active tetrameric form of p53 in the nuclei of living cells and the destabilization of native-drifted p53 species that become amyloid. Collectively, these results provide insights into the role of amyloid-like mutant p53 oligomers in the chemoresistance phenotype of malignant and invasive brain tumors and shed light on therapeutic options to avert cancer.

The Status of p53 Oligomeric and Aggregation States in Cancer

“…The ∆40p53 isoform in endometrial carcinoma has shown aggregation tendencies [54]. Mutant p53 oligomeric species larger than its tetrameric form have been detected in the nuclei in vivo, as well as evidence of tetramers in the cytosol [43]. The particular p53 mutation examined in the study is highly expressed, and accumulates as amyloid oligomers in glioblastoma cells presenting a chemoresistant phenotype [43].…”

“…Mutant p53 oligomeric species larger than its tetrameric form have been detected in the nuclei in vivo, as well as evidence of tetramers in the cytosol [43]. The particular p53 mutation examined in the study is highly expressed, and accumulates as amyloid oligomers in glioblastoma cells presenting a chemoresistant phenotype [43]. It is plausible that some mutant p53 quaternary compositions, such as those depicted in Figure 3, could be involved in targeting of p53 to novel REs involved with chemoresistance genes.…”

“…This gain of oncogenic function promotes increased microglia and inflammation in the central nervous system, accelerating glioblastoma progression and treatment resistance [58]. Similarly, amyloid aggregates of mutant p53 have been linked to temozolomide chemoresistance in aggressive glioblastoma [43]. Cancer cells presenting a chemoresistance p53 mutation display a GoF mechanism by over-expressing MGMT, an O 6 -methylguanine DNA-methyltransferase, that repairs DNA damage caused by temozolomide [43,59] ( Figure 3C).…”

“…Fluorescence correlation spectroscopy (FCS) showed that under resting conditions, a chemoresistant p53 mutant showed a higher population of cytosolic tetramers, compared to wild-type p53 [43]. Gaglia et al [44] quantified the fraction of p53 monomers, dimers, and tetramers in living cells under resting and post-DNA damage conditions.…”

“…Mutations within its DBD can make p53 more susceptible to form oligomeric species with amyloid-like features and oncogenic activities [50]. Aggregated species of mutant p53, and different p53 isoforms have been reported in cancer cells presenting GoF phenotypes [43,[50][51][52][53]; however, their correlation with oncogenic activities in cancer requires clarification [4]. The ∆40p53 isoform in endometrial carcinoma has shown aggregation tendencies [54].…”