Parathyroid hormone-related protein regulates apoptosis in lung cancer cells through protein kinase A

Abstract

Parathyroid hormone-related protein (PTHrP)-(1–34) and PTHrP-(140–173) protect lung cancer cells from apoptosis after ultraviolet (UV) irradiation. This study evaluated upstream signaling in PTHrP-mediated alteration of lung cancer cell sensitivity to apoptosis. The two peptides increased cAMP levels in BEN lung cancer cells by 15–35% in a dose-dependent fashion, suggesting signaling through protein kinase A (PKA). In line with this view, the PKA inhibitor H89 abrogated the protective effects of PTHrP-(1–34) and PTHrP-(140–173) against caspase activation and DNA loss. PKA activation by forskolin, 3-isobutyl-1-methylxanthine (IBMX), or 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate attenuated and H89 augmented apoptosis after UV exposure as indicated by caspase-3 activation, cell DNA loss, and morphological criteria. Studies with IBMX and varying doses of forskolin indicated that small increases in cAMP, on the order of those generated by IBMX alone and the PTHrP peptides, were sufficient to protect lung cancer cells from apoptosis. In summary, PTHrP-(1–34) and PTHrP-(140–173) stimulate PKA in lung carcinoma cells and protect cells against UV-induced caspase-3 activation and DNA fragmentation. PKA activation by other means also induces resistance to apoptosis, and the protective effect of the PTHrP peptide is blocked by PKA inhibition. Thus PKA appears to have a role in the regulatory effects of PTHrP on lung cancer cell survival.

Trps1 plays a pivotal role downstream of Gdf5 signaling in promoting chondrogenesis and apoptosis of ATDC5 cells

“…It was reported that Pthrp inhibits apoptosis in cartilage (Yamanaka et al . 2003) and in lung tumors (Hastings et al . 2004).…”

Parathyroid-hormone-related protein signaling mechanisms in lung carcinoma growth inhibition

“…Since PTH1R stimulates cAMP as its second messenger in H1944 cells (Hastings et al 2009) and BEN lung cancer cells (Hastings et al 2004; Kukreja et al 1988; Pizurki et al 1988), we investigated the direct effects of cell-permeant cAMP compounds on H1944 cell growth. 8-CPT-cAMP, a non-selective analog, inhibited the rise in cell number in a time- and dose-dependent manner (Figure 2a, b).…”

“…We have previously shown that PTH1R activation was coupled to Gs and generation of cAMP in H1944 cells and BEN lung cancer cells, rather than Gq pathways (Hastings et al 1996, 2004, 2009). When cell-permeant cAMP analogs were tested in this study, they mimicked the effect of PTHrP in inhibiting H1944 cell growth.…”

Stimulatory heterotrimeric GTP‐binding protein augments cisplatin‐induced apoptosis by upregulating Bak expression in human lung cancer cells

“…However, the effect of the Gαs–cAMP signaling system on apoptosis was different among lung cancer cells. The Gαs–cAMP signaling system protects lung cancer cells from ultraviolet radiation‐induced apoptosis ( 28 ) and plays an important role in cell growth and survival of H1734 non‐small cell lung cancer cells. ( 29 ) Therefore, it is essential to investigate the mechanisms that determine the effects of the cAMP signaling system on the cell death of lung cancer cells for the development of a new strategy to increase the therapeutic effect of cytotoxic drugs or radiation by modifying the cAMP signaling system.…”