Parathyroid Hormone-Related Protein Regulates Cell Survival Pathways via Integrin α6β4-Mediated Activation of Phosphatidylinositol 3-Kinase/Akt Signaling

Bhatia, Vandanajay; Mula, Ramanjaneya V.R.; Weigel, Nancy L.; Falzon, Miriam

doi:10.1158/1541-7786.mcr-08-0568

Cited by 40 publications

(39 citation statements)

References 52 publications

(83 reference statements)

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“…Similar results were reported by Falzon and collaborators [44] in a study on human prostate cancer cell lines. It is known that prostate carcinogenesis is characterized by the increase of PTHrP secretion [45] which was proven to up-regulate integrin α6β4, capable to activate the PI3K pathway when signaling synergistically with growth factor receptors such as ErbB2, ErbB3, and c-Met.…”

Section: Pthrp As a Stimulator Of Cell Survival And Proliferation Ofsupporting

confidence: 91%

Parathyroid Hormone-Related Protein (PTHrP): A Key Regulator of Life/Death Decisions by Tumor Cells with Potential Clinical Applications

Luparello

2011

Cancers

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Parathyroid hormone-related protein (PTHrP), classically regarded as the mediator of the humoral hypercalcemia of malignancy syndrome, is a polyhormone that undergoes proteolytic processing into smaller bioactive forms. These bioactive forms comprise an N-terminal-as well as midregion-and C-terminal peptides, which have been shown to regulate various biological events, such as survival, proliferation and differentiation, in diverse cell model systems, both normal and pathological. A number of experimental data have demonstrated that PTHrP is also able to modulate tumor-relevant phenotypic expressions, thereby playing a role in early and advanced tumorigenesis, and in the response to treatment. In particular, interest has mainly been focused on the effects of PTHrP on cell proliferation/apoptosis, migration and invasion, which are the main roles involved in cancer development in vivo. The objective of this review is to discuss collectively the literature data on the molecular and biochemical basis of the mechanisms underlying the different, and sometimes opposite, effects exerted by PTHrP on various neoplastic cytotypes, with some final comments on both present and potential utilization of PTHrP as a target for anti-cancer therapy.

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Section: Pthrp As a Stimulator Of Cell Survival And Proliferation Ofsupporting

confidence: 91%

Parathyroid Hormone-Related Protein (PTHrP): A Key Regulator of Life/Death Decisions by Tumor Cells with Potential Clinical Applications

Luparello

2011

Cancers

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“…Notably, this was the first time that PI3K had been implicated in carcinoma invasion. This finding was subsequently confirmed in a number of additional reports (39–41), although the exact mechanism by which integrin α6β4 activates PI3K initially remained elusive. The cytoplasmic domain of the integrin β4 subunit does not contain a consensus-binding motif for the regulatory subunit of PI3K, making direct activation of this pathway by integrin β4 subunit unlikely (4, 6, 42).…”

Section: Integrin α6β4 Signaling In Malignant Cellsmentioning

confidence: 66%

“…If anchorage to the ECM is lost, the subsequent loss of integrin signaling can inhibit cell growth and promote a specialized form of apoptosis referred to as anoikis (63). While tumor suppressive functions of the integrin β4 subunit have been identified in bladder (64), colon (65), and breast carcinoma (66) cell lines, a number of additional studies have indicated that the β4 integrin promotes cell survival (19, 41, 66–68). This dichotomy appears to hinge on the expression and mutation status of the p53 tumor suppressor.…”

Section: Integrin α6β4 Signaling In Malignant Cellsmentioning

confidence: 99%

Clinical significance of the integrin α6β4 in human malignancies

Stewart

O’Connor

2015

Laboratory Investigation

177

181

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Integrin α6β4 is a cellular adhesion molecule that binds to laminins in the extracellular matrix and nucleates the formation of hemidesmosomes. During carcinoma progression, integrin α6β4 is released from hemidesmosomes, where it can then signal to facilitate multiple aspects of tumor progression including sustaining proliferative signaling, tumor invasion and metastasis, evasion of apoptosis, and stimulation of angiogenesis. The integrin achieves these ends by cooperating with growth factor receptors including EGFR, ErbB-2, and c-Met to amplify downstream pathways such as PI3K, AKT, MAPK and the Rho family small GTPases. Furthermore, it dramatically alters the transcriptome toward a more invasive phenotype by controlling promoter DNA demethylation of invasion and metastasis-associated proteins, such as S100A4 and autotaxin, and upregulates and activates key tumor promoting transcription factors such as the NFATs and NFkB. Expression of integrin α6β4 has been studied in many human malignancies where its overexpression is associated with aggressive behavior and a poor prognosis. This review provides an assessment of integrin α6β4 expression patterns and their prognostic significance in human malignancies, and describes key signaling functions of integrin α6β4 that contribute to tumor progression.

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“…PTHLH interacts with parathyroid hormone/parathyroid hormone-related protein receptor (PTH/PTHLH type 1 receptor, PTH1R), a member of family B G-protein coupled receptor, and controls several cellular function through activation of the cAMP/PKA or IP 3 /PKC signaling cascades. PTHLH promotes cell proliferation, migration, and invasion, and prevents apoptosis in different types of cancers91011. In HNSCC, PTHLH has been reported as a poor prognostic marker and is stimulated in vitro cell growth through promoting cell cycle progression12.…”

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confidence: 99%

Parathyroid Hormone-Like Hormone is a Poor Prognosis Marker of Head and Neck Cancer and Promotes Cell Growth via RUNX2 Regulation

Chang

Lin

et al. 2017

Sci Rep

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Parathyroid Hormone-Like Hormone (PTHLH) is an autocrine/paracrine ligand that is up-regulated in head and neck squamous cell carcinoma (HNSCC). However, the cellular function and regulatory mechanism in HNSCC remains obscure. We investigated the clinical significance of PTHLH in HNSCC patients, and verified the role of RUNX2/PTHLH axis, which is stimulated HNSCC cell growth. In patients, PTHLH is a poor prognosis marker. PTHLH expression lead to increasing the cell proliferation potential through an autocrine/paracrine role and elevating blood calcium level in Nod-SCID mice. In public HNSCC microarray cohorts, PTHLH is found to be co-expressed with RUNX2. Physiologically, PTHLH is regulated by RUNX2 and also acting as key calcium regulator. However, elevations of calcium concentration also increased the RUNX2 expression. PTHLH, calcium, and RUNX2 form a positive feedback loop in HNSCC. Furthermore, ectopic RUNX2 expression also increased PTHLH expression and promoted proliferation potential through PTHLH expression. Using cDNA microarray analysis, we found PTHLH also stimulated expression of cell cycle regulators, namely CCNA2, CCNE2, and CDC25A in HNSCC cells, and these genes are also up-regulated in HNSCC patients. In summary, our results reveal that PTHLH expression is a poor prognosis marker in HNSCC patients, and RUNX2-PTHLH axis contributes to HNSCC tumor growth.

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Parathyroid Hormone-Related Protein Regulates Cell Survival Pathways via Integrin α6β4-Mediated Activation of Phosphatidylinositol 3-Kinase/Akt Signaling

Abstract: Parathyroid hormone-related protein (PTHrP) is expressed by human prostatic tissues and cancer cell lines. PTHrP enhances tumor cell growth and metastasis in vivo and up-regulates proinvasive integrin α 6 β 4 expression in vitro.

Cited by 40 publications

References 52 publications

Parathyroid Hormone-Related Protein (PTHrP): A Key Regulator of Life/Death Decisions by Tumor Cells with Potential Clinical Applications

Parathyroid Hormone-Related Protein (PTHrP): A Key Regulator of Life/Death Decisions by Tumor Cells with Potential Clinical Applications

Clinical significance of the integrin α6β4 in human malignancies

Parathyroid Hormone-Like Hormone is a Poor Prognosis Marker of Head and Neck Cancer and Promotes Cell Growth via RUNX2 Regulation

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