Activation of TAp73 and inhibition of thioredoxin reductase for improved cancer therapy inTP53 mutant pancreatic tumors

Abstract

1The p73 is a tumor suppressor that compensates for p53 loss and induces apoptosis in 2 tumors in response to genotoxic stress or small-molecule treatments.3 Pancreatic ductal adenocarcinoma (PDAC) has a late onset of the disease, responds 4 poorly to the existing therapies and has very low overall survival rates. 5Here, using drug-repurposing approach, we found that protoporphyrin IX (PpIX) and 6 benzoporphyrin derivative monoacid ring A (BPD) activate p73 and induce apoptosis 7 in pancreatic cancer cells. PpIX and BPD induce reactive oxygen species and inhibit 8 thioredoxin reductase 1 (TrxR1). Thus, PpIX and BPD target cancer cells' 9 vulnerabilities namely activate TAp73 tumor suppressor and inhibit oncogenic TrxR1. 1 0Our findings, may contribute to faster repurposing of PpIX and BPD to treat 1 1 pancreatic tumors. 1 2 Lay Abstract 1 3Despite the efforts, pancreatic cancer remains among the most aggressive tumors.

Protoporphyrin IX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and induces apoptosis in B-cell chronic lymphocytic leukaemia cells

“…In cancer cells, in addition to PUMA and BAX, PpIX induced the expression of heme oxygenase HMOX-1 (Figure 3A), a stress response gene. This is in agreement with the previous studies showing that PpIX induces antioxidant response in cancer cells 12 . PpIX is an inhibitor of thioredoxin reductase (TrxR), a selenoprotein that plays a critical role in the oxidoreductase system and is often overexpressed in cancers.…”

“…In addition, induction of HMOX-1 stress response gene, suggests induction of ROS in EHEB cells. We, alongside others, showed that PpIX is an inhibitor of thioredoxin reductase, a key enzyme of the thioredoxin antioxidant defence system12,40,56 . Inhibition of TrxR leads to induction of ROS, thus we speculate that PpIX induces HMOX-1 in EHEB cells by activating stress response pathway due to inhibition of TrxR.…”

“…PpIX is an inhibitor of thioredoxin reductase (TrxR), a selenoprotein that plays a critical role in the oxidoreductase system and is often overexpressed in cancers. Inhibition of TrxR by PpIX induces reactive oxygen species (ROS) in cancer cells, triggers antioxidant response and contributes to cancer cell death 12,40 . Thus, we speculate that PpIX induces p53-and TAp73-dependent apoptosis and ROS in B-CLL cells without affecting non-transformed cells.…”

“…In drug repurposing approach PpIX was identified as an activator of p53 and TAp73α tumor suppressors. Recent work demonstrates that PpIX inhibits TAp73/MDM2 and TAp73/MDM4 interactions, which leads to stabilisation of TAp73 protein and induction of TAp73-dependent apoptosis in cancers with TP53 gene mutations 11,12 .…”

“…TAp73-dependent apoptosis in cancers with TP53 gene deletions or mutations12,29 . This is in agreement with previous studies showing that colon cancer cells harbouring wtTP53 gene are more sensitive to photodynamic therapy with Photofrin®, a derivative of hematoporphyrin and, a close structural analog of PpIX 54 .…”