Blocking mutation independent p53 aggregation by emodin modulates autophagic cell death pathway in lung cancer.

Loss of p53 function via mutation is a very common cause of human cancers. Recent studies have provided evidence on presence of self aggregated p53 in cancer cells leading to its altered functions towards cause of cancer. The general notion has been that mutated p53 exposes adhesive sites that promote self aggregation, however a complete mechanistic understanding to this has been lacking. We embarked on the present study towards exploring the differential aggregation pattern in cells expressing mutated TP53 (HaCaT keratinocytes) vs those expressing the wild type copy of the p53 protein (A549 lung cancer cell line). The studies led us to interesting observation that formation of p53 protein aggregates is not always associated with TP53 mutation. The A549 lung cancer cells, having wild type TP53, showed the appearance of p53 protein aggregates, while no protein aggregates were observed in normal HaCaT keratinocytes carrying mutant TP53. We went on to study the effect of blocking protein aggregation by emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) and figured that inhibiting p53 protein aggregation can elevate the level of autophagy in A549 lung cancer cell line while there is no significant effect on autophagy in normal non-cancerous HaCaT cells. Moreover, ATG5 was found to be coaggregated with p53 aggregates which dissociated after emodin treatment, indicating further induction of autophagy in A549 cells only. From these observations, we conclude that the increased level of autophagy might be the mechanism for the removal of p53 protein aggregates which restores p53 function in A549 cells after emodin treatment .This encourages further studies towards deciphering related mechanistic aspects vis-à-vis potential therapeutic strategies against cancer.