Parathyroid hormone-related protein enhances PC-3 prostate cancer cell growth via both autocrine/paracrine and intracrine pathways

Sepúlveda, Verónica A. Tovar; Falzon, Miriam

doi:10.1016/s0167-0115(02)00007-1

Cited by 63 publications

(38 citation statements)

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“…PTHrP acts via both autocrine/paracrine and intracrine pathways [9,10,18,26], and the PTHrP-mediated effects reported here may be mediated via either or both of these pathways. 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].…”

Section: Discussionsupporting

confidence: 65%

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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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Section: Discussionsupporting

confidence: 65%

“…The same may apply to LoVo cells. However, the effects of PTHrP on the migration, invasion, and apoptosis of MCF-7 cells appear to be mediated via an intracrine pathway [26,51]. Thus, PTHrP may regulate the various parameters which define tumor aggression via different pathways, and the pathway(s) utilized may be cell-specific.…”

Section: Discussionmentioning

confidence: 99%

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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“…Bombesin and calcitonin each exert a proliferative effect on the androgen-independent PC-3 and DU-145 prostate cancer cell lines (Bologna et al, 1989;Jongsma et al, 2000;Larran et al, 2000), as well as stimulation of PC3 cell migration (Aprikian et al, 1997). Cell growth and DNA synthesis are increased when prostate cancer cells are stimulated with PTHrP (Iwamura et al, 1994;Tovar-Sepulveda and Falzon, 2002). Proliferation and DNA synthesis of PC3 cells (Seethalakshmi et al, 1997;Lee et al, 2001;Hassan and Carraway, 2006), and also of LNCaP cells in the absence of androgen (Sehgal et al, 1994;Lee et al, 2001), are stimulated when cells are treated with NT.…”

Section: Introductionmentioning

confidence: 99%

“…Proliferation and DNA synthesis of PC3 cells (Seethalakshmi et al, 1997;Lee et al, 2001;Hassan and Carraway, 2006), and also of LNCaP cells in the absence of androgen (Sehgal et al, 1994;Lee et al, 2001), are stimulated when cells are treated with NT. Receptors for bombesin (Reile et al, 1994;Aprikian et al, 1996;Xiao et al, 2002), NT (Seethalakshmi et al, 1997;Dal Farra et al, 2001;Petit et al, 2001) and PTHrP (Tovar-Sepulveda and Falzon, 2002) are expressed by PC3, LNCaP and/or DU145 prostate cancer cells and have been characterized with respect to proliferative function. Thus, mitogenic neuropeptides that are secreted by NE-like cells can activate specific membrane-bound receptors on the surface of prostate cancer cells, resulting in increased proliferation and DNA synthesis.…”

Section: Introductionmentioning

confidence: 99%

Neurotensin stimulates mitogenesis of prostate cancer cells through a novel c-Src/Stat5b pathway

2006

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Neuroendocrine (NE)-like cells are hypothesized to contribute to the progression of prostate cancer by producing factors that enhance the growth, survival or metastatic capabilities of surrounding tumor cells. Many of the factors known to be secreted by NE-like cells, such as neurotensin (NT), parathyroid hormone-related peptide, serotonin, bombesin, etc., are agonists for G-proteincoupled receptors, but the signaling pathways activated by these agonists in prostate tumor cells are not fully defined. Identification of such pathways could provide insights into novel methods of treating late-stage disease. Using conditioned culture medium (CM) from LNCaPderived NE-like cells (as a source of these agonists) or NT (a prototypical component of CM) to treat PC3 cells, we found that the epidermal growth factor (EGF) receptor (EGFR) was transactivated and that such activation was required for maximal PC3 cell mitogenesis, as measured by 5-bromo-2 0 -deoxy-uridine incorporation or cell number. NT also induced a time-dependent increase in EGFR Tyr 845 phosphorylation and phosphorylation of c-Src and signal transducer and activator of transcription 5b (Stat5b) (a downstream effector of Tyr 845 ), events that were blocked by specific inhibition of c-Src (which mediates Tyr 845 phosphorylation of EGFR) or of EGFR. Introduction of mutant forms of EGFR (Tyr 845 ) or Stat5b in PC3 cells, or treatment with selective, catalytic inhibitors of EGFR, c-Src and matrix metalloproteinases (MMPs) resulted in the loss of NT-induced stimulation of DNA synthesis, relative to wild-type controls. These data indicate that the mitogenic effect of NT on prostate cancer cells requires transactivation of the EGFR by MMPs and a novel downstream pathway involving c-Src, phosphorylation of EGFR Tyr 845 and activation of Stat5b.

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“…1). CaR-stimulated secretion of PTHrP could offer a selective advantage by contributing to tumor cell survival and growth and/or skeletal complications (e.g., osteolysis), as PTHrP has been shown to promote growth and survival of tumors that secrete it (95,96).…”

Section: Humoral Hypercalcemia Of Malignancy and The Role Of Pthrpmentioning

confidence: 99%

Effects of calcium-sensing receptor on the secretion of parathyroid hormone-related peptide and its impact on humoral hypercalcemia of malignancy

Chattopadhyay¹

2006

American Journal of Physiology-Endocrinology and Metabolism

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Chattopadhyay, Naibedya. Effects of calcium-sensing receptor on the secretion of parathyroid hormone-related peptide and its impact on humoral hypercalcemia of malignancy. Am J Physiol Endocrinol Metab 290: E761-E770, 2006; doi:10.1152/ajpendo.00350.2005.-The extracellular calcium-sensing receptor (CaR) plays a key role in the defense against hypercalcemia by "sensing" extracellular calcium (Ca 2ϩ o) levels in the parathyroid and kidney, the key organs maintaining systemic calcium homeostasis. However, CaR function can be aberrant in certain pathophysiological states, e.g., in some types of cancers known to produce humoral hypercalcemia of malignancy (HHM) in humans and animal models in which high Ca 2ϩ o, via the CaR, produces a homeostatically inappropriate stimulation of parathyroid hormone-related peptide (PTHrP) secretion from these tumors. Increased levels of PTHrP set a cycle in motion whereby elevated systemic levels of Ca 2ϩ o resulting from its increased bone-resorptive and positive renal calcium-reabsorbing effects give rise to hypercalcemia, which in turn begets worsening hypercalcemia by stimulating further release of PTHrP by the cancer cells. I review the relationship between CaR activation and PTHrP release in normal and tumor cells giving rise to HHM and/or malignant osteolysis and the actions of the receptor on key cellular events such as proliferation, angiogenesis, and apoptosis of cancer cells that will favor tumor growth and osseous metastasis. I also illustrate diverse signaling mechanisms underlying CaR-stimulated PTHrP secretion and other cellular events in tumor cells. Finally, I raise several necessary questions to demonstrate the roles of the receptor in promoting tumors and metastases that will enable consideration of the CaR as a potential antagonizing/ neutralizing target for the treatment of HHM.G protein-coupled receptor; osteolysis; metastasis; cytokine; receptor tyrosine kinase HUMORAL HYPERCALCEMIA OF MALIGNANCY AND THE ROLE OF PTHRPHYPERCALCEMIA IS USUALLY DEFINED as a state in which serum calcium concentrations are greater than 12 mg/dl, corrected for serum albumin concentration. Hypercalcemia frequently arises from primary hyperparathyroidism or in the context of various malignancies including, most frequently, breast, prostate, lung, and renal carcinomas (for review see Ref. 41). Many factors, including vascular endothelial growth factor (VEGF) and interleukin-8 and -11, have been implicated in promoting hypercalcemia of malignancy (41). However, parathyroid hormonerelated peptide (PTHrP) has now been shown to be the major pathogenic factor (31, 98 -100). This is because the tumor burden and bone lesions have been shown to be decreased significantly by treatment with PTHrP-neutralizing antibody in mice inoculated with a human breast cancer cell line ] or lung squamous cell carcinoma-derived cells [HARA (44)]. When produced in excess by extraskeletal tumor cells, i.e., in humoral hypercalcemia of malignancy (HHM), PTHrP spills into the systemic circulation and acts on the s...

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Parathyroid hormone-related protein enhances PC-3 prostate cancer cell growth via both autocrine/paracrine and intracrine pathways

Cited by 63 publications

References 35 publications

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

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

Neurotensin stimulates mitogenesis of prostate cancer cells through a novel c-Src/Stat5b pathway

Effects of calcium-sensing receptor on the secretion of parathyroid hormone-related peptide and its impact on humoral hypercalcemia of malignancy

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