Opposing mitogenic and anti-mitogenic actions of parathyroid hormone-related protein in vascular smooth muscle cells: A critical role for nuclear targeting

Massfelder, Thierry; Dann, Pamela; Wu, Terence; Vasavada, Rupangi C.; Helwig, Jean-Jacques; Stewart, Andrew F.

doi:10.1073/pnas.94.25.13630

Cited by 216 publications

(233 citation statements)

References 37 publications

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“…They clearly demonstrated that PTHrP possesses a double signalling on MCF-7: an antimitogenic pathway mediated by the membrane receptor and a second wave of signalling, pro-proliferative and antiapoptotic, based on nuclear localisation of the peptide. The same dual effect had also been described in vascular smooth muscle cells in 1997 (Massfelder et al, 1997).…”

Section: Sirsupporting

confidence: 73%

PTHrP on MCF-7 breast cancer cells: a growth factor or an antimitogenic peptide?

Maioli

Fortino

2004

Br J Cancer

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Section: Sirsupporting

confidence: 73%

PTHrP on MCF-7 breast cancer cells: a growth factor or an antimitogenic peptide?

Maioli

Fortino

2004

Br J Cancer

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“…We have previously shown that PTHrP modulates cell proliferation via both the autocrine/paracrine and intracrine pathways in MCF-7 human breast cancer cells and PC-3 human prostate cancer cells [50,51]. Similar effects on proliferation have been reported for vascular smooth muscle cells [52]. The same may apply to LoVo cells.…”

Section: Discussionsupporting

confidence: 60%

Increased cell survival, migration, invasion, and Akt expression in PTHrP-overexpressing LoVo colon cancer cell lines

Shen¹,

Mula²,

Evers³

et al. 2007

Regulatory Peptides

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Parathyroid hormone-related protein (PTHrP) has been localized in human colon cancer tissue and cell lines. We have previously shown that PTHrP increases colon cancer cell proliferation, extracellular matrix adhesion, and cell-surface integrin α6β4 expression. Since cancer cell migration, invasion, and survival are crucial components of metastasis, and colon cancer has a high metastatic potential, in this study we used the human colon cancer cell line LoVo as a model system to study the effects of PTHrP on these parameters. PTHrP expression was modulated by stable transfection with a construct expressing PTHrP (−36 to +139). We report that PTHrP increases cell migration, invasion, and survival. PTHrP altered cell morphology, with PTHrP-overexpressing cells exhibiting increased spreading and several long protrusions. PTHrP also increased the steady-state mRNA levels of the integrin α6 and β4 subunits, indicating a direct and/or indirect effect of PTHrP on the transcriptional and/or posttranscriptional regulation of integrin α6 and β4 expression. Integrin α6β4 activates the phosphoinositol 3-kinase (PI3-K)/Akt pathway, leading to glycogen synthase kinase-3 (GSK-3) deactivation. PTHrP overexpression also led to an increase in active Akt and inactive GSK-3 levels, indicating that the PTHrP-mediated upregulation of integrin α6β4 expression may activate the PI3-K pathway, resulting in increased cell survival, migration and invasion.

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“…37 In cells, other than breast cancer, NLS in PTHrP has been shown to be required for growth. For example in vascular smooth muscle cells, nuclear targeting of PTHrP was reported to be pivotal in mitogenesis 27 and in chondrocytes nuclear localisation promoted protection from apoptosis. 25 When the influence of PTHrP-(67-101) in MCF-7 cells incubated with taxotere was examined, it was found that PTHrP-(67-101) did not significantly increase the percentage of cells resistant to taxotere-induced apoptosis, which possibly suggests that it has a growth-promoting role rather than a survival role in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…35 for review) and has been shown to be required for growth in various cells types. 25,27,28 The role of midregion in breast cancer has only recently been investigated. 29 In our study we show that midregion PTHrP containing NLS spanning amino acid sequences of 87 to 101, is essential for midregion-induced growth in breast cancer cells such as MCF-7 and MDA-MB231.…”

Section: Discussionmentioning

confidence: 99%

“…For example, in chondrocytes, nucleolar localisation of PTHrP was shown to have a protective role against apoptosis induced by serum starvation 25 and in vascular smooth muscle (VSM) cells, nuclear entry resulted in proliferation. 27 In MCF-7 cells overexpressing NLS-mutated PTHrP-(1-139), a marked inhibition of growth was observed as a result of insufficient nuclear localisation. 28 Studies using midregion PTHrP-(67-94) lacking the full NLS demonstrated anti-growth and anti-invasive roles in breast cancer cells, 29,30 although nuclear targeting was not investigated.…”

mentioning

confidence: 99%

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Nuclear targeting of a midregion PTHrP fragment is necessary for stimulating growth in breast cancer cells

Kumari

Robertson

Watson

2006

Intl Journal of Cancer

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Parathyroid-hormone related protein (PTHrP) is the primary factor in humoral hypercalcemia of malignancy and is highly secreted by breast cancers. The pro-hormone undergoes posttranslational processing and cleavage to give rise to mature secretory peptides, one of which is midregion PTHrP (38-94/95/101) containing a nuclear localisation sequence (NLS) in amino acids (87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97)(98)(99)(100)(101)(102)(103)(104)(105)(106). The current study investigates whether the NLS in midregion PTHrP is important in breast cancer growth. PTHrP-(67-101), a midregion PTHrP fragment containing NLS-(87-101) significantly increased growth of MCF-7 and MDA-MB231 cells (126.3 and 121.3% of control respectively in serum conditions), independent of PTHR1 whereas PTHrP-(67-86), which lacks the NLS did not. Fluorescent-labelled PTHrP-(67-101) translocated to the nucleus, whereas PTHrP-(67-86) remained cytosolic and a scrambled(1NLS) peptide was not internalised. In comparison, no growth influence or uptake was seen in non-tumour breast cells (Hs578Bst). Increases in intracellular calcium mobilisation were observed in breast cancer cells stimulated with both PTHrP-(67-101) and PTHrP-(67-86) (EC 50 of 3.2 pM and 2.2 pM respectively for MCF-7 cells), whereas inositide turnover was not detected. Both nuclear uptake and calcium signalling were attenuated in the presence of EGTA, but not with U73122 or N-terminal PTHrP peptides. Our studies indicate that the NLS-containing midregion PTHrP peptide is dependent on both internalisation and nuclear translocation to induce growth in breast cancer cells. These findings highlight the importance of midregion PTHrP and its receptor in breast cancer growth and may provide potential targets for future therapeutic intervention. ' 2006 Wiley-Liss, Inc.Key words: PTHrP; breast cancer; NLS; calcium signalling; midregion PTHrP Parathyroid hormone-related protein (PTHrP) was first identified as a tumour-derived protein that was the primary factor in humoral hypercalcemia of malignancy (HHM). 1-3 The first 13 amino acids of PTHrP and parathyroid hormone (PTH) share significant homology 4,5 and it is this sequence which interacts with the parathyroid hormone receptor 1 (PTHR1). 6 As a result, tumour-derived PTHrP enters the circulation and activates PTHR1 in both the bone and kidney to induce PTH-like activity, the outcome of which is hypercalcaemia and osteoclast-mediated bone resorption. 1,2,7 PTHrP is expressed in breast epithelium and is associated with normal mammary gland function, cell growth and differentiation. [8][9][10][11][12] Studies using PTHrP knockout mice resulted in mammary epithelial cell degeneration, 13 emphasising the importance of PTHrP in breast growth. Breast cancers, in most cases, secrete high levels of PTHrP, [14][15][16] and as a result malignancy associated HHM is very common. The expression of PTHrP has also been reported to be higher in breast cancer skeletal metastases than in the primary tumour. 14,17,18 The role of PTHrP may therefore be biolog...

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Opposing mitogenic and anti-mitogenic actions of parathyroid hormone-related protein in vascular smooth muscle cells: A critical role for nuclear targeting

Cited by 216 publications

References 37 publications

PTHrP on MCF-7 breast cancer cells: a growth factor or an antimitogenic peptide?

PTHrP on MCF-7 breast cancer cells: a growth factor or an antimitogenic peptide?

Increased cell survival, migration, invasion, and Akt expression in PTHrP-overexpressing LoVo colon cancer cell lines

Nuclear targeting of a midregion PTHrP fragment is necessary for stimulating growth in breast cancer cells

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