Abstract
Poly (ADP-ribose) polymerases (PARPs) modify target proteins with a single ADP-ribose unit or with a poly (ADP-ribose) (PAR) polymer. PARP inhibitors (PARPis) recently became clinically available for the treatment of BRCA1/2 deficient tumors via the synthetic lethality paradigm. This personalized treatment primarily targets DNA damage-responsive PARPs (PARP1-3). However, the biological roles of PARP family member enzymes are broad; therefore, the effects of PARPis should be viewed in a much wider context, which includes complex effects on all known hallmarks of cancer. In the companion paper (part 1) to this review, we presented the fundamental roles of PARPs in intrinsic cancer cell hallmarks, such as uncontrolled proliferation, evasion of growth suppressors, cell death resistance, genome instability, replicative immortality, and reprogrammed metabolism. In the second part of this review, we present evidence linking PARPs to cancer-associated inflammation, anti-cancer immune response, invasion, and metastasis. A comprehensive overview of the roles of PARPs can facilitate the identification of novel cancer treatment opportunities and barriers limiting the efficacy of PARPi compounds.
Highlights
In two seminal papers, Hanahan and Weinberg proposed a set of quintessential traits that define cancer [1,2]
One of the most interesting aspects concerning the role of Poly (ADP-ribose) polymerases (PARPs)-1 in tumor immunology was a report demonstrating upregulation of the immunosuppressive cancer cell ligand PD-L1 in breast cancer cells treated with the PARP inhibitors, olaparib, talazoparib, and rucaparib [151]
The most detailed picture we have is about the proinflammatory role of PARP-1
Summary
Hanahan and Weinberg proposed a set of quintessential traits that define cancer [1,2] Six of these cancer hallmarks describe altered behaviors of transformed cells compared to their normal counterparts. According to these six hallmarks, cancer cells are characterized by genomic instability, sustained proliferative signaling, evasion of growth-suppressive signals, replicative immortality, altered metabolism, and resistance to cell death. In addition to these intrinsic cancer cell traits, four additional hallmarks/enabling characteristics define interactions between cancer tissue and the host organism [1]. In addition to the delivery of oxygen, nutrients, and growth factors, the neovasculature provides communication channels for cancerous cells to disseminate [13]
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