Mutant P53 Harboring Luminal-A Breast Cancer Cells Are Refractory to Apoptosis and Cell Cycle Arrest in Response to Mortaparib, a Multimodal Small Molecule Inhibitor

We previously performed a drug screening to identify a potential inhibitor of mortalin-p53 interaction. In four rounds of screenings based on the shift in mortalin immunostaining pattern from perinuclear to pan-cytoplasmic and nuclear enrichment of p53, we had identified Mortaparib (4-[(1E)-2-(2-phenylindol-3-yl)-1-azavinyl]-1,2,4-triazole) as a novel synthetic small molecule. In order to validate its activity and mechanism of action, we recruited Luminal-A breast cancer cells, MCF-7 (p53) and T47D (p53) and performed extensive biochemical and immunocytochemical analyses. Molecular analyses revealed that Mortaparib is capable of abrogating mortalin-p53 interaction in both MCF-7 and T47D cells. Intriguingly, upregulation of transcriptional activation function of p53 (as marked by upregulation of the p53 effector gene--responsible for cell cycle arrest and apoptosis) was recorded only in Mortaparib-treated MCF-7 cells. On the other hand, Mortaparib-treated T47D cells exhibited hyperactivation of PARP1 (accumulation of PAR polymer and decrease in ATP levels) as a possible non-p53 tumor suppression program. However, these cells did not show full signs of either apoptosis or PAR-Thanatos. Molecular analyses attributed such a response to the inability of Mortaparib to disrupt the AIF-mortalin complexes; hence, AIF did not translocate to the nucleus to induce chromatinolysis and DNA degradation. These data suggested that the cancer cells possessing enriched levels of such complexes may not respond to Mortaparib. Taken together, we report the multimodal anticancer potential of Mortaparib that warrants further attention in laboratory and clinical studies.