Exploring the Role of Prostaglandin G/H Synthase Signalling in Chemoresistance in Acute Myeloid Leukaemia

Abstract

Antioxidant signalling is demonstrated to be important for leukemic stem cell (LSC) and haematopoietic stem cell (HSC) function. HSCs, which are found in the bone marrow, are found to be more quiescent under hypoxic conditions. Reduced cell division creates problems for these cells, with the majority of cells using this process to address oxidative damaged DNA and proteins. In this situation, HSCs must approach oxidative damage management in other ways. Prostaglandins improve mechanisms to protect from oxidative stresses through causing reductions in reactive oxygen species (ROS). Prostaglandin G/H synthases (PTGS1/2) play the main role in catalysing synthesis of prostaglandins. Research has demonstrated that PGE2, produced through PTGS1/2 activity, assists HSCs in surviving, proliferating and homing within their niche. Similarly, the data provided in this study points to a protective function of PTGS1/2 signal pathways for acute myeloid leukaemia. PTGS genes were investigated for their association with outcomes in AML, in an approach combining biochemistry, bioinformatics, molecular biology and cellular biology. Analysis of bioinformatics databases aimed to assess how PTGS1/2 was expressed in AML and the effects of this expression on outcomes including overall survival. An efficacy assessment was made for PTGS1 inhibitors (SC560, Tenidap) for AML cell lines. Flow cytometry was used to evaluate the cell cycle and apoptosis. Lentiviral PTGS1/2 over-expression was used for U937 and HL-60 in order to assess how these genes act in cell survival, proliferative activity and resistance to drugs. Finally, PTGS1/2 was analysed in terms of promotion of immunosuppression in acute myeloid leukaemia. Investigation of freely accessible bioinformatics databases demonstrated increased PTGS1 expression in the HSC, which reduced in cells committed to a lineage for myeloid progenitor cells. This was not found for PTGS2. There is a notable association between increased expression of PTGS1 and lower overall survival in data on AML (TCGA, Verhaak), with none seen for PTGS2. Findings in vitro show that inhibiting PTGS1 (SC560, Tenidap) leads to decreased growth of cells, arrests the cell cycle and elevates apoptosis. Overexpressed PTGS1 leads to higher WNT signalling for AML cell lines, as well as raising PGE2 secretions and reversing PTGS1 inhibitor impacts. Other effects of increased PTGS1 expression include resistance to cytarabine, as linked with lower generation of ROS. It is notable that overexpression of PTGS1 and PTGS2 lead to significant differences in transcriptome alterations in AML, which could explain the varied patient outcomes with PTGS1/2 overexpression.