Parathyroid hormone-related protein ameliorates death receptor-mediated apoptosis in lung cancer cells

Abstract

Parathyroid hormone-related protein (PTHrP) is expressed in more advanced, aggressive tumors and may play an active role in cancer progression. This study investigated the effects of PTHrP on apoptosis after UV irradiation, Fas ligation, or staurosporine treatment in BEN human squamous lung carcinoma cells. Cells at 70% confluency were treated for 24 h with 100 nM PTHrP-(1-34), PTHrP-(38-64), PTHrP-(67-86), PTHrP-(107-139), or PTHrP-(140-173) in media with serum, exposed for 30 min to UV-B radiation (0.9 mJ/cm2), and maintained for another 24 h. Caspase-3, caspase-8, and caspase-9 activities increased fivefold. Pretreatment with PTHrP-(1-34) and PTHrP-(140-173) ameliorated apoptosis after UV irradiation, as indicated by reduced caspase activities, increased cell protein, decreased nuclear condensation, and increased clonal survival. Other peptides had no effect on measures of apoptosis. PTHrP-(140-173) also reduced caspase activities after Fas ligation by activating antibody, but neither peptide had effects on caspase-3 or caspase-9 activity after 1 μM staurosporine. These data indicate that PTHrP-(1-34) and PTHrP-(140-173) protect against death receptor-induced apoptosis in BEN lung cancer cells but are ineffective against mitochondrial pathways. PTHrP contributes to lung cancer cell survival in culture and could promote cancer progression in vivo. The mechanism for the protective effect against apoptosis remains to be determined.

Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34

“…The antiapoptotic properties of PTHrP have been observed in a variety of cell types (20,(31)(32)(33)(34)(35)(36)(37). While the molecular mechanisms by which PTHrP signaling in the osteoblast prevents apoptotic cell death remain to be determined, a number of them may be operative.…”

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

“…PTHrP demonstrates widespread distribution in lung carcinomas, being present in a high percentage of lung tumors (13) of all histological types (4). In addition, PTHrP is an autocrine growth factor for lung cancer cells (5) and protects them from apoptosis (11), characteristics that could contribute to a cancer's capacity for unregulated growth. Furthermore, PTHrP induces expression of metalloproteinases in carcinoma cells and may stimulate angiogenesis in tumors (3,17) These factors are important in providing a carcinoma with the means to develop its blood supply, to invade into adjacent tissues, and to metastasize.…”

“…A recent study (11) reported that the PTHrP-derived peptide PTHrP-(140 -173) exerts regulatory effects on lung cancer cell apoptosis. Pretreatment with 100 nM PTHrP-(140 -173) for 24 h protected BEN human squamous lung carcinoma cells from the apoptotic effects of ultraviolet (UV)-B irradiation or activating Fas antibody (11).…”

Combinatorial library discovery of small molecule inhibitors of lung cancer proliferation and parathyroid hormone-related protein expression

“…Cells were plated at 5,000 cells/well in 96-well plates in growth media for proper cell adherence. 8 The following day, cells were incubated in serum free media with 1 mg/ml BSA overnight for synchronization of cell growth cycle. The experiment was initiated by transferring cells to growth media with appropriate treatments.…”

“…PTHrP increases the likelihood of bone metastases in mice injected with small cell lung carcinoma cells 7 and it protects squamous lung carcinoma cells from apoptosis. 8 Since PTHrP is expressed in two-thirds or more of non-small cell lung carcinomas in humans, 9 it could be a reasonable target for a lung cancer therapy.…”