PARP-1/2 Inhibitor Olaparib Prevents or Partially Reverts EMT Induced by TGF-β in NMuMG Cells

Abstract

Poly- adenosine diphosphate (ADP)-ribose (PAR) is a polymer synthesized as a posttranslational modification by some poly (ADP-ribose) polymerases (PARPs), namely PARP-1, PARP-2, tankyrase-1, and tankyrase-2 (TNKS-1/2). PARP-1 is nuclear and has also been detected in extracellular vesicles. PARP-2 and TNKS-1/2 are distributed in nuclei and cytoplasm. PARP or PAR alterations have been described in tumors, and in particular by influencing the Epithelial- Mesenchymal Transition (EMT), which influences cell migration and drug resistance in cancer cells. Pro-EMT and anti-EMT effects of PARP-1 have been reported while whether PAR changes occur specifically during EMT is currently unknown. The PARP-1/2 inhibitor Olaparib (OLA) is approved by FDA to treat certain patients harboring cancers with impaired homologous recombination. Here, we studied PAR changes and OLA effects on EMT. Total and nuclear PAR increased in EMT while PAR belts were disassembled. OLA prevented EMT, according to: (i) molecular markers evaluated by immuno-cytofluorescence/image quantification, Western blots, and RNA quantitation, (ii) morphological changes expressed as anisotropy, and (iii) migration capacity in the scratch assay. OLA also partially reversed EMT. OLA might work through unconventional mechanisms of action (different from synthetic lethality), even in non-BRCA (breast cancer 1 gene) mutated cancers.

LAIR-1 overexpression inhibits epithelial–mesenchymal transition in osteosarcoma via GLUT1-related energy metabolism

“…Recent studies have indicated that the STC-1 gene is closely related to glucose and lipid metabolism as well as to mitochondrial function [29,30]. In addition, PARP or PAR alterations have been described in tumors, speci cally those in uencing EMT [31][32][33]. Our RNA-seq and qPCR results strongly suggest that LAIR-1 inhibits EMT through metabolic pathways.…”

LAIR-1 overexpression inhibits epithelial–mesenchymal transition in osteosarcoma via GLUT1-related energy metabolism

“…Recent studies have indicated that the STC-1 gene is closely related to glucose and lipid metabolism as well as to mitochondrial function [29,30]. In addition, PARP or PAR alterations have been described in tumors, specifically those influencing EMT [31][32][33]. Our RNA-seq and qPCR results strongly suggest that LAIR-1 inhibits EMT through metabolic pathways.…”

Down-regulation of PADI2 prevents proliferation and epithelial-mesenchymal transition in ovarian cancer through inhibiting JAK2/STAT3 pathway in vitro and in vivo, alone or in combination with Olaparib

“…Single treatment of them reduced N-Cadherin and Vimentin, but increased claudin-1 and 2 to inhibit EMT. Schacke et al [ 25 ] reported that olaparib prevented the occurrence of EMT. McElwee [ 20 ] reported that overexpression of PADI2 in mice led to occur EMT in tumor cells, which decreased E-Cadherin expression and increased Snail and Vimentin expression.…”

“…Among them, single treatment reduced n-cadherin and Vimentin, but increased claudin-1 and -2 to inhibit EMT. Schack et al [ 25 ]reported that Olaparib prevented EMT from occurring. Furthermore, Chen et al [ 26 ]found that PADI2 was closely related to the process of EMT.…”