Leuprorelin acetate affects ERK1/2 activity in prostate cancer cells

Iacopino, Fortunata; Lama, Gina; Angelucci, Cristiana; Sica, Gigliola

doi:10.3892/ijo.29.1.237

Cited by 9 publications

(9 citation statements)

References 28 publications

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“…In this paradigm, BRCA2 seems to function by exercising a stringent control upon cell proliferation capable of positive and negative feedback in the normal cellular environment, and its absence due to neoplastic cell transformation results in unchecked cell proliferation that is triggered by PI 3-kinase/ AKT signaling after cell interaction with the ECM. These results would support recent reports suggesting a role for activated ERK in mediating drug-induced apoptosis or inhibition of cell proliferation in PC-3, as well as ovarian and breast cancer cells (43)(44)(45)(46)(47).…”

Section: Discussionsupporting

confidence: 91%

Constitutive activation of MAPK/ERK inhibits prostate cancer cell proliferation through upregulation of BRCA2

Moro¹,

Arbini²,

Marra³

et al. 2007

Int J Oncol

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Abstract. BRCA2 is central to an utterly diverse biological behavior elicited after integrin-mediated normal and prostate cancer cell adhesion to basement membrane (BM) and extracellular matrix (ECM) proteins. Unlike normal cells, adhesive stimuli in cancer cells activate PI 3-kinase/AKT signaling resulting in BRCA2 degradation and unchecked cancer cell proliferation and metastasis. However, the precise mechanisms involved in normal BRCA2 homeostasis are unknown. We investigated ERK and AKT phosphorylation in normal (PNT1A) and cancer (PC-3) prostate cells after adhesion to ECM and the effects upon BRCA2 and cell proliferation. PNT1A cell adhesion to ECM triggered MAPK/ERK signaling resulting in upregulation of BRCA2 mRNA and protein, with negligible effects upon cell proliferation. Disruption of MAPK/ERK with PD98059 prevented any BRCA2 upregulation inhibiting DNA synthesis below basal levels. PC-3 cells exhibited a defective MAPK/ERK pathway that was unresponsive to adhesion to the ECM, which instead triggered PI 3-kinase/AKT signaling leading to BRCA2 protein depletion and cell proliferation. Reconstitution of MAPK/ERK by recombinant expression of a constitutively active form of MAPK kinase 1 (MEK1) effectively reversed the neoplastic phenotype by increasing BRCA2 expression and preventing any aberrant cell proliferation at rest and upon interaction with ECM proteins. Our results suggest that aberrant loss of MAPK/ERK activity in prostate cancer may play a pivotal role in the malignant phenotype, and provide evidence that interventions aimed at bypassing the signaling block are able to effectively reverse neoplastic unchecked cell proliferation. IntroductionIn adult human prostate, the relationship between cell proliferation and cell death is a precise balancing act that prevents organ involution or overgrowth. Upon neoplastic transformation this equilibrium is ultimately deranged leading to abnormal organ growth and tumor formation (1). Both processes are exquisitely regulated by a continuous cross-talk between cells and the surrounding microenvironment. Chemical stimuli such as growth factors or physical interaction with BM or ECM proteins activate diverse cell signaling pathways that exert control over cell proliferation and survival (2-5). The MAPK/ERK (mitogen-activated protein kinase/ extracellularregulated kinase) and PI 3-kinase (phosphatidyl inositol 3-kinase)/AKT signaling pathways are two major transducers of extracellular stimuli through modulation of the expression of genes exerting stringent control upon cell survival, motility, and cell proliferation (6,7). ERK accumulation in the nucleus regulates transcription factors involved in DNA synthesis (8), cell differentiation (9,10), and promotion of acinar formation in the normal prostate (11). Similarly, the PI 3-kinase/AKT signaling pathway regulates many cellular processes that are critically involved in cell proliferation and survival (12). The role of these pathways in oncogenesis has been extensively investigated and altered expression/activi...

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Section: Discussionsupporting

confidence: 91%

Constitutive activation of MAPK/ERK inhibits prostate cancer cell proliferation through upregulation of BRCA2

Moro¹,

Arbini²,

Marra³

et al. 2007

Int J Oncol

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“…The antitumor efficacy of GnRH agonists in peripheral tissues depends, amongst others, on the cross-talk with growth factor signaling cascades [21,24,39]. GnRH agonist direct inhibition of PCa growth acts by attenuating a well-documented autocrine proliferation signaling loop.…”

Section: Discussionmentioning

confidence: 99%

“…In a series of studies on these cell lines, we have also demonstrated the ability of the GnRH agonist Leuprorelin acetate (LA) to downregulate PSA gene expression and to induce variations in apoptosis-related gene expression [18][19][20]. More recently, the ability of LA to counteract the EGF-induced ERK1/2 activation in LNCaP cells has been demonstrated by our group [21].…”

Section: Introductionmentioning

confidence: 94%

GnRH receptor expression in human prostate cancer cells is affected by hormones and growth factors

Angelucci

Lama

Iacopino

et al. 2009

Endocr

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GnRH receptors (GnRH-R) have been found in various malignancies, including prostate cancer (PCa). They mediate the direct antitumor effects of GnRH analogs. Nevertheless, few reports concern drug-induced modulation of GnRH-R levels. In this study, we investigated GnRH-R expression in androgen-sensitive (LNCaP) and -insensitive (PC-3) PCa cells treated for 4 and 6 days with a GnRH agonist (Leuprorelin acetate, LA, 10(-11) or 10(-6) M), Dihydrotestosterone (DHT, 10(-9) M), Cyproterone acetate (CA, 10(-7) M), and Epidermal growth factor (EGF, 10 ng/ml), either alone or combined. The RT-PCR analysis showed no variation in GnRH-R mRNA levels of both treated LNCaP and PC-3 cells. On the contrary, immunoblotting indicated that in LNCaP and PC-3 cells, LA upregulated membrane GnRH-R expression (up to 92%). In androgen-sensitive cells, DHT induced a GnRH-R increase (up to 119%) always comparable to that occurring in the presence of CA. GnRH-R upregulation by LA/DHT or CA/DHT association was similar to that promoted by the single agents. In PC-3 cells, EGF upregulated GnRH-R (up to 110%). A prolonged treatment (for 12 days) determined a greater EGF-induced increase in GnRH-R levels (142%). Lower (or no) receptor enhancement occurred when LA and EGF were associated. Our findings indicate that LA post-transcriptionally upregulates its own membrane receptor in androgen-sensitive and -insensitive PCa cells, counteracting the receptor enhancement produced by DHT and EGF. The effects, obtained with a relatively long and continuous treatment, may have implications in the choice of therapy modality with GnRH analogs and may render the receptor a novel therapeutic target, particularly in hormone-refractory PCa.

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“…In fact, antagonistic effects were observed on tumor cell growth as well as on the expression of PsA, MAP kinases, apoptosis-related genes and GnRH-R (22)(23)(24)(25)(26)(27)(28)(29). The molecular basis of the interference between DHT and LA is still unclear but conceivably could be ascribed to the analogue targeting of the androgen receptor (AR) signaling.…”

Section: Discussionmentioning

confidence: 99%

“…In our experience, GnRH agonists are ineffective in regulating cell growth when used alone, but they counteract or suppress the stimulation of cell proliferation induced by estrogens in mammary and endometrial cancer cells (22)(23)(24) and by androgens or epidermal growth factor (EGF) in CaP cells (25). In the same CaP cells, we demonstrated the ability of the GnRH agonist, leuprorelin acetate (LA), to modulate the expression of various genes and/or proteins correlated with growth, differentiation and apoptosis and to up-regulate GnRH-R (25)(26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 92%

Leuprorelin acetate affects adhesion molecule expression in human prostate cancer cells

Angelucci

Lama²,

Iacopino³

et al. 2011

Int J Oncol

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Abstract. Reduced cell-cell adhesion allows malignant epithelial cells to invade the basal membrane and penetrate the stroma. This implies the potential of the cells to escape from the primary tumor as well as spreading ability. Herein, we investigated the effects of leuprorelin acetate (LA), a GnRH agonistic analogue, alone or in combination with dihydrotestosterone (DHT), on the expression of molecules involved in cell adhesion (E-cadherin, N-cadherin, α-, β-and γ-catenin) or in migration/invasion (c-met, CD44v6 and caveolin-1) in androgen-sensitive (LNCaP) and -insensitive (PC-3) prostate cancer (CaP) cells. We demonstrated by immunoblotting that, in LNCaP cells, molecules present in the adherens junctions (E-cadherin, α-, β-and γ-catenin) were expressed, while α-catenin was absent in PC-3 cells which expressed N-cadherin and c-met. In LNCaP cells, no changes in E-cadherin levels were produced by 10 -9 M DHT while LA (10 -11 or 10 -6 M) up-regulated the protein level (up to 26-30% after 48 h). In the same cells, β-and γ-catenin expression was enhanced either by DHT (24 and 20%, respectively) or LA (up to 18 and 40%, respectively), while α-catenin was not affected. Antagonistic effects were consistently observed between DHT and LA when the two hormones were jointly administered to the cells. Consistent results were obtained by immunocytochemistry. Co-immunoprecipitation analysis, used to verify the integrity of the LNCaP cell adhesion complex, demonstrated the association of E-cadherin with catenins. In PC-3 cells, adhesion molecule expression, analyzed by immunoblotting, was unaffected by LA, while a down-regulation of c-met (up to 28%) was observed after 24 h of treatment but which did not hold up over time (48-144 h). Our findings demonstrate the efficacy of LA in upregulating E-cadherin, β-and γ-catenin in LNCaP cells. This effect, that may be considered as another aspect of the direct antitumor activity of the GnRH analogue in hormone-dependent CaP cells, may contribute to maintenance/restoration of the normal tissue architecture counteracting the tumor cell spreading tendency.

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Leuprorelin acetate affects ERK1/2 activity in prostate cancer cells

Cited by 9 publications

References 28 publications

Constitutive activation of MAPK/ERK inhibits prostate cancer cell proliferation through upregulation of BRCA2

Constitutive activation of MAPK/ERK inhibits prostate cancer cell proliferation through upregulation of BRCA2

GnRH receptor expression in human prostate cancer cells is affected by hormones and growth factors

Leuprorelin acetate affects adhesion molecule expression in human prostate cancer cells

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