punicalagin and Thyroid-Neoplasms

Papillary thyroid carcinoma (PTC) is the most common endocrine carcinoma. Our previous study revealed that punicalagin (PUN), an active component from pomegranate, triggered autophagic cell death and DNA damage response (DDR) in papillary thyroid carcinoma BCPAP cells. But the detailed anti-cancer mechanisms of punicalagin against PTC still remained to be further explored. DDR activation is a proven cause of cellular senescence, which mediates anti-tumor processes under certain circumstances. In this study, we reported that punicalagin treatment generated a senescent phenotype of BCPAP cells characterized as altered morphology, increased cell granularity and senescence-associated β-galactosidase (SA-β-Gal) staining. Senescence induced by punicalagin treatment was further confirmed by cell cycle arrest and upregulation of cyclin-dependent kinase inhibitor p21. Meanwhile, the senescence-associated secretory phenotype (SASP) included high levels of inflammatory cytokines, principally IL-6 and IL-1β. Furthermore, punicalagin exposure caused the phosphorylation and subsequent degradation of IκBα as well as the nuclear translocation of p65, suggesting the activation of NF-κB signaling pathway. Inhibition of NF-κB by pyrrolidine dithiocarbamate (PDTC), a selective inhibitor of NF-κB, partially reversed the cellular senescent phenotype induced by punicalagin in BCPAP cells as evidenced by the decreased fraction of SA-β-Gal staining positive cells and blockage of SASP generation. These results collectively showed that punicalagin treatment induced senescent growth arrest and SASP via triggering NF-κB activation. These observations elucidated novel anti-cancer mechanisms of punicalagin and might provide new potential prospects for PTC therapy.

Topics: Carcinoma, Papillary; Cell Cycle Checkpoints; Cell Line, Tumor; Cellular Senescence; Dose-Response Relationship, Drug; Humans; Hydrolyzable Tannins; NF-kappa B; Signal Transduction; Thyroid Cancer, Papillary; Thyroid Neoplasms

Punicalagin (PUN), a component derived from pomegranate, is well known for its anticancer activity. Our previous work revealed that PUN induces autophagic cell death in papillary thyroid carcinoma cells. We hypothesized that PUN triggers DNA damage associated with cell death because DNA damage was reported as an inducer of autophagy. Our results showed that PUN treatment caused DNA breaks as evidenced by the significant enhancement in the phosphorylation of H2A.X. However, reactive oxygen species and DNA conformational alteration, 2 common inducing factors in DNA damage, were not involved in PUN-induced DNA damage. The phosphorylation of ataxia-telangiectasia mutated gene-encoded protein (ATM) but not ataxia telangiectasia and Rad3-related protein (ATR) was up-regulated in a time- and dosage-dependent manner after PUN treatment. KU-55933, an inhibitor of ATM, inhibited the phosphorylation of ATM induced by PUN and reversed the decreased cell viability caused by PUN. Thus, we demonstrated that PUN induces cell death of papillary thyroid carcinoma cells by triggering ATM-mediated DNA damage response, which provided novel mechanisms and potential targets for the better understanding of the anticancer actions of PUN.

Topics: Ataxia Telangiectasia Mutated Proteins; Carcinoma, Papillary; Cell Death; Cell Line, Tumor; Cell Survival; DNA Damage; Gene Expression Regulation; Humans; Hydrolyzable Tannins; Lythraceae; Phosphorylation; Thyroid Cancer, Papillary; Thyroid Neoplasms