Proapoptotic Effects of Parathyroid Hormone-Related Protein in Type II Pneumocytes

Hastings, Randolph H.; Quintana, Rick; Sandoval, Rebeca; Duey, Devin; Rascon, Yvette; Burton, Douglas W.; Deftos, Leonard J.

doi:10.1165/rcmb.2002-0314oc

Cited by 15 publications

(9 citation statements)

References 34 publications

(49 reference statements)

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“…In contrast, PTHrP-(1-34) is proapoptotic in HEK-293 embryonic human kidney cells by acting through a G q -mediated phospholipase C-Ca 2ϩ signaling pathway (33). In alveolar epithelial cells, protective effects against apoptosis are apparently mediated through a PKC-dependent pathway (13). Further work is necessary to establish the signaling mechanisms for PTHrP-(1-34) and PTHrP-(140-173) in lung cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Nuclear condensation was quantified as described previously (13). Adherent cells in Slide-Tek wells were washed with PBS and fixed with 100% methanol.…”

Section: Measurementsmentioning

confidence: 99%

“…Thus studies of UV radiation-induced apoptosis may elucidate mechanisms common to lung cancer cell apoptosis in a variety of settings, including DNA damage after chemotherapy or radiation. We initially measured caspase-3 activity in cells treated with peptides spanning the entire PTHrP sequence, because biological activity has been ascribed to multiple portions of the molecule (11,13,23,24,30,34). Two peptides inhibited caspase-3, PTHrP-(1-34) and PTHrP-(140-173), and were evaluated further for effects on caspase-8 activity, caspase-9 activity, and nuclear fragmentation/condensation.…”

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confidence: 99%

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

Hastings¹,

Araiza²,

Burton³

et al. 2003

American Journal of Physiology-Cell Physiology

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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.

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Section: Discussionmentioning

confidence: 99%

“…Nuclear condensation was quantified as described previously (13). Adherent cells in Slide-Tek wells were washed with PBS and fixed with 100% methanol.…”

Section: Measurementsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

Hastings¹,

Araiza²,

Burton³

et al. 2003

American Journal of Physiology-Cell Physiology

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“…cAMP and inositol phosphates were measured with protocols described previously (12). Cells were washed twice with PBS and incubated for 30 min in serum-free medium before application of agonists.…”

Section: Second Messenger Assaysmentioning

confidence: 99%

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

Hastings¹,

Araiza²,

Burton³

et al. 2004

American Journal of Physiology-Cell Physiology

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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.

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“…For example, PTHrP 67-86 has antimitogenic effects on selected breast carcinoma cell lines (18,19). We recently demonstrated that PTHrP 1-34 and PTHrP 67-86 both sensitize type II cells to apoptosis after exposure to ultraviolet radiation (13). Both peptides cause a rapid increase in pneumocyte inositol phosphate levels.…”

Section: Discussionmentioning

confidence: 99%

Amino-terminal and midmolecule parathyroid hormone-related protein, phosphatidylcholine, and type II cell proliferation in silica-injured lung

Hastings

Quintana²,

Sandoval³

et al. 2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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Acute silica lung injury is marked by alveolar phospholipidosis and type II cell proliferation. Parathyroid hormone-related protein (PTHrP) 1-34 could have a regulatory role in this process because it stimulates phosphatidylcholine secretion and inhibits type II cell growth. Other regions of the PTHrP molecule may have biological activity and can also exert pulmonary effects. This study examined the temporal pattern for expression of several regions of PTHrP after silica lung injury and evaluated the effects of changes in expression on cell proliferation and lung phospholipids. Expression of all PTHrP regions fell at 4 days after injury. Reversing the decline in PTHrP 1-34 or PTHrP 67-86 with one intratracheal dose and four daily subcutaneous doses of PTHrP 1-34 or PTHrP 67-86 stimulated bronchoalveolar lavage disaturated phosphatidylcholine (DSPC) levels. Cell culture studies indicate that the peptides exerted direct effects on DSPC secretion by type II cells. Neither peptide affected type II cell proliferation with this dosing regimen, but addition of an additional intratracheal dose resulted in significant inhibition of growth, consistent with previous effects of PTHrP 1-34 in hyperoxic lung injury. These studies establish a regulatory role for PTHrP 1-34 and PTHrP 67-86 in DSPC metabolism and type II cell proliferation in silica injury. Growth inhibitory effects of PTHrP could interact with phospholipid stimulation by affecting type II cell numbers. Further studies are needed to explore the complex interactions of PTHrP-derived peptides and the type II cell response at various stages of silica lung injury. adult respiratory distress syndrome; cell surface receptors; pulmonary surfactant; silicosis; type II pneumocyte ALVEOLAR TYPE II EPITHELIAL cells produce parathyroid hormone-related protein (PTHrP) (11) and express the type I PTH/PTHrP receptor (15). PTHrP 1-34, a ligand of this receptor, stimulates synthesis and secretion of disaturated phosphatidylcholine (DSPC) (15) and inhibits type II cell growth in culture and in vivo (16). The autocrine effects of PTHrP play a role in regulating the type II cell response to hyperoxic lung injury. Lung PTHrP levels fall early after exposure to 85% oxygen, concomitant with the onset of type II cell proliferation, and then return to baseline as proliferation slows (9,14). Furthermore, intratracheal administration of exogenous PTHrP 1-34 during the period when endogenous lung levels are low reduces pneumocyte growth (9). Lung PTHrP levels also decrease after injury due to 100% oxygen (14), suggesting that decreases may be a generalized response to injury. The effect of PTHrP on proliferation of type II cells after other types of injury has not received extensive investigation, and the role of PTHrP in regulating lung phospholipids in injury has not been reported.Instillation of silica into the lungs of rats produces a model of acute silicosis marked by accumulation of pulmonary phospholipids and alveolar type II cell hyperplasia and hypertrophy (20,23,24). Extracellula...

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Proapoptotic Effects of Parathyroid Hormone-Related Protein in Type II Pneumocytes

Cited by 15 publications

References 34 publications

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

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

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

Amino-terminal and midmolecule parathyroid hormone-related protein, phosphatidylcholine, and type II cell proliferation in silica-injured lung

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