PARP activity and expression in response to DNA damage in mice with lung cancer-induced cachexia

Lung cancer (LC) is a major leading cause of death worldwide and cachexia is a frequent comorbidity. Poly (ADP ribose) polymerases (PARP)-1 and PARP-2 are important players in cancer regulating chromatin structure. PARP activity is also involved in muscle mass maintenance and metabolism. We hypothesized that in a mouse preclinical model of LC-induced cachexia, DNA damage is increased along with PARP activity and expression. We aimed to evaluate: 1) body weight and muscle function, 2) DNA damage, 3) PARP activity levels and 4) PARP-1 and PARP-2 protein expression in lung tumor samples of BALB/c cachectic mice. Lung tumors (subcutaneous inoculation of 4×105 LP07 adenocarcinoma cells) were harvested from the lungs of wild-type BALB/c mice: non-tumor control mice and tumor-bearing mice (N=9/group). DNA damage (immunohistochemistry), PARP activity (PARP colorimetric assay kit assay), and PARP-1 and PARP-2 expression (immunoblotting) were identified in lung tumor samples, and body and muscle function were also assessed. Compared to non-tumor control lungs, in lung tumor samples, DNA damage increased, while PARP activity and PARP-1 protein expression decreased. Limb muscle function significantly impaired in lung cancer cachexia mice. In lung tumors of wild type mice in this experimental model of LC cachexia, PARP activity along with PARP-1 expression decreased, while greater DNA damage levels were observed. These results have potential clinical implications as PARP inhibitors are currently in use for the treatment of breast and ovarian cancer types, in which cachexia and muscle dysfunction are very prominent. Funding: FIS 18/00075 (FEDER, ISC-III), CIBERES (ISC-III), SEPAR 2018 & 2020.