Dysregulation of lysophospholipid signaling by p53 in malignant cells and the tumor microenvironment

The TP53 gene has been widely studied for its roles in cell cycle control, maintaining genome stability, activating repair mechanisms upon DNA damage, and initiating apoptosis should repair mechanisms fail. Thus, it is not surprising that mutations of p53 are the most common genetic alterations found in human cancer. Emerging evidence indicates that dysregulation of lipid metabolism by p53 can have a profound impact not only on cancer cells but also cells of the tumor microenvironment (TME). In particular, intermediates of the sphingolipid and lysophospholipid pathways regulate many cellular responses common to p53 such as cell survival, migration, DNA damage repair and apoptosis. The majority of these cellular events become dysregulated in cancer as well as cell senescence. In this review, we will provide an account on the seminal contributions of Prof. Lina Obeid, who deciphered the crosstalk between p53 and the sphingolipid pathway particularly in modulating DNA damage repair and apoptosis in non-transformed as well as transformed cells. We will also provide insights on the integrative role of p53 with the lysophosphatidic acid (LPA) signaling pathway in cancer progression and TME regulation. •There is a complex interplay between the p53 and sphingolipid signaling modulating DDR toward metabolic and genotoxic stress.•LPA signalling regulats p53 via transcriptional regulation of Autotaxin that generates LPA from tumor cells and cells of the tumor microenvironment.•A novel hypothesis is proposed for the role of p53 in the reprograming of Autotaxin production in the cells of the tumor microenvironment.