Parathyroid hormone‐related peptide can regulate the growth of human lung cancer cells, and may form part of an autocrine TGF‐α loop

Burton, Paul; Knight, D. E.

doi:10.1016/0014-5793(92)80674-6

Cited by 34 publications

(17 citation statements)

References 26 publications

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“…In addition, PTH-rP has been shown to play a role in causing cachexia in tumorbearing mice. 5 Alternatively, several previous studies have demonstrated that PTH-rP is an autocrine growth factor for tumors such as rat Walker 256 carcinoma 27 and BEN human lung carcinoma, 28 both of which are associated with hypercalcemia. More recently, it has been reported that PTH-rP promotes the progression and metastases of rat malignant pituitary tumor 23 and human prostate carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Parathyroid hormone‐related protein measured at the time of first visit is an indicator of bone metastases and survival in lung carcinoma patients with hypercalcemia

Hiraki

Ueoka

Bessho

et al. 2002

Cancer

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BACKGROUNDParathyroid hormone‐related protein (PTH‐rP) is a major cause of tumor‐induced hypercalcemia (TIH) and frequently is found to be elevated in serum of patients with TIH. In the current study, the authors examined the usefulness of PTH‐rP measurement at the time of first presentation in the follow‐up of lung carcinoma patients with TIH.METHODSThe authors retrospectively studied 23 of 1149 lung carcinoma patients who were found to have TIH at the time of first presentation for the correlation between serum PTH‐rP and the development of bone metastases and survival compared with lung carcinoma patients without TIH who were matched by gender, age, Eastern Cooperative Oncology Group performance status, histological type of tumor, and stage of the disease.RESULTSTwenty‐three lung carcinoma patients with TIH demonstrated significantly increased serum levels of PTH‐rP (mean ± standard error [SE], 84.1 ± 16.5 pmol/L) compared with control patients without TIH (mean ± SE, 36.2 ± 2.0 pmol/L) at the time of first presentation, (P < 0.001). In these hypercalcemic patients, patients whose serum PTH‐rP was > 150 pmol/L (n = 16) were found to have a significantly increased rate of bone metastases (71.4% vs. 12.5%; P = 0.01) and decreased survival (median survival of 1.4 months vs. 5.4 months; P < 0.015) compared with patients whose serum PTH‐rP was < 150 pmol/L (n = 7).CONCULUSIONSThe data from the current study suggest that serum PTH‐rP as determined at the time of first presentation is a useful indicator of not only hypercalcemia but also bone metastasis and eventual survival in patients with lung carcinoma. Cancer 2002;95:1706–13. © 2002 American Cancer Society.DOI 10.1002/cncr.10828

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Section: Discussionmentioning

confidence: 99%

Parathyroid hormone‐related protein measured at the time of first visit is an indicator of bone metastases and survival in lung carcinoma patients with hypercalcemia

Hiraki

Ueoka

Bessho

et al. 2002

Cancer

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“…Peptide growth factor agonists for the EGFR include epidermal growth factor (EGF), transforming growth factor α (TGFα,) amphiregulin (AREG), heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC), epiregulin (EPR) and epigen (EPG) [17]. Consequently, exogenous application of EGF and TGFα activated PTHrP gene expression in many types of epithelial cells [18][19][20][21]. Indeed, autocrine expression of AREG and consequent stimulation of EGFR signaling appears to account for the high levels of PTHrP produced by cultured keratinocytes [14].…”

Section: Introductionmentioning

confidence: 99%

Amphiregulin-EGFR signaling regulates PTHrP gene expression in breast cancer cells

Gilmore

Scott

Bouizar

et al. 2007

Breast Cancer Res Treat

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Parathyroid hormone-related protein (PTHrP) is an autocrine/paracrine factor produced by breast cancer cells that is speculated to play a major role in permitting breast cancer cells to grow into the bone microenvironment by stimulating the bone resorption axis. It has been previously shown that EGFR signaling induces the production of PTHrP in several primary and transformed epithelial cell types. Therefore, we investigated the relationship between EGFR and PTHrP gene expression in human breast cancer cells. Of a panel of 7 breast epithelial and cancer cell lines, the osteolytic, EGFRpositive lines (MDA-MB-231 and NS2T2A1) exhibited higher levels of PTHrP transcript expression. Amphiregulin mRNA levels in all lines were approximately 2 orders of magnitude higher than those of TGFα or HBEGF. In the EGFR bearing lines, the receptor was phosphorylated at tyrosine 992 under basal conditions, and the addition of 100 nM amphiregulin did not lead to the phosphorylation of other tyrosine residues typically phosphorylated by the prototypical ligand EGF. Treatment of the EGFR positive lines with the EGFR inhibitor PD153035 and amphiregulin-neutralizing antibodies reduced PTHrP mRNA levels by 50-70%. Stable EGFR expression in the MCF7 line failed to increase basal PTHrP mRNA levels; however, treatment of this cell line with exogenous EGF or amphiregulin increased PTHrP transcription 3-fold. Transient transfection analysis suggests that the MAPK pathway and ETS transcription factors mediate EGFR coupling to PTHrP gene expression. Taken together, it appears that autocrine stimulation of EGFR signaling by amphiregulin is coupled to PTHrP gene expression via EGFR Tyr992 and MAPK, and that this pathway may contribute to PTHrP expression by breast tumor cells.

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“…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.…”

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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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Parathyroid hormone‐related peptide can regulate the growth of human lung cancer cells, and may form part of an autocrine TGF‐α loop

Cited by 34 publications

References 26 publications

Parathyroid hormone‐related protein measured at the time of first visit is an indicator of bone metastases and survival in lung carcinoma patients with hypercalcemia

Parathyroid hormone‐related protein measured at the time of first visit is an indicator of bone metastases and survival in lung carcinoma patients with hypercalcemia

Amphiregulin-EGFR signaling regulates PTHrP gene expression in breast cancer cells

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

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