Antagonist of growth hormone-releasing hormone induces apoptosis in LNCaP human prostate cancer cells through a Ca
            <sup>2+</sup>
            -dependent pathway

Rékási, Zoltán; Czömpöly, Tamás; Schally, Andrew V.; Boldizsár, Ferenc; Varga, József; Zarándi, Márta; Berki, Tímea; Horváth, Réka; Németh, Pèter

doi:10.1073/pnas.0410006102

Cited by 33 publications

(28 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This may cause some saturation in the corresponding signaling pathways and, after supplementation with exogenous GHRH, results in their down-regulation. Considering the recently reported antiapoptotic effect of GHRH on cancer cells (21), it could be argued that serum deprivation may be sufficient to trigger apoptosis in MCF-7 cells, thus complicating the interpretation of our experimental results. However, apoptosis appears unlikely because, under our experimental conditions, no evidence of cell death was noted after 4 days of culture in the absence of serum, despite the dramatic reduction in the baseline levels of cell proliferation.…”

Section: Discussionmentioning

confidence: 93%

Stimulation of proliferation of MCF-7 breast cancer cells by a transfected splice variant of growth hormone-releasing hormone receptor

Barabutis

Tsellou

Schally

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Recent evidence indicates that growth hormone-releasing hormone (GHRH) functions as an autocrine/paracrine growth factor for various human cancers. A splice variant (SV) of the full-length receptor for GHRH (GHRHR) is widely expressed in various primary human cancers and established cancer cell lines and appears to mediate the proliferative effects of GHRH. To investigate in greater detail the role of SV1 in tumorigenesis, we have expressed the full-length GHRHR and its SV1 in MCF-7 human breast cancer cells that do not possess either GHRHR or SV1. In accordance with previous findings, the expression of both GHRHR and SV1 restored the sensitivity to GHRH-induced stimulation of cell proliferation, with SV1 being more potent than the GHRHR. Furthermore, MCF-7 cells transfected with SV1 proliferated more quickly than the controls, even in the absence of exogenously added GHRH, suggesting the existence of intrinsic, ligand-independent activity of SV1 after its transfection. In agreement with the stimulation of cell proliferation, the levels of proliferation markers cyclin D1, cyclin E, and proliferating cell nuclear antigen were elevated in MCF-7 cells treated with GHRH, cultured in both serum-free and serumcontaining media. In addition, SV1 caused a considerable stimulation of the ability of MCF-7 cells to grow in semisolid medium, an assay considered diagnostic for cell transformation. Collectively, our findings show that the expression of SV1 confers oncogenic activity and provide further evidence that GHRH operates as a growth factor in breast cancer and probably other cancers as well.carcinogenesis ͉ intrinsic activity ͉ transfection G rowth hormone-releasing hormone (GHRH), produced by the hypothalamus, regulates the secretion of growth hormone (GH) by binding to specific receptors in the pituitary (1). In addition to this neuroendocrine action, recent studies also indicate that GHRH functions as an autocrine/paracrine growth factor in various cancers (2-5). The evidence for this concept includes the detection of GHRH expression in several extrapituitary tissues, especially primary human cancers and experimental tumors, and the ability of antagonistic analogs of GHRH to inhibit cancer cell growth by mechanisms that do not involve the GH-induced stimulation of production of hepatic insulin-like growth factor I (2-6).Our understanding of how GHRH acts in extrapituitary tissues, and especially cancers, is restricted by poor functional characterization of the receptor(s) that mediates its mitogenic effects, especially in view of the limited expression of GHRH receptor (GHRHR) by extrapituitary tissues (7-9). Recently, it has been demonstrated that a splice variant (SV) of GHRHR (designated SV1, which differs from GHRHR in a short segment of the extracellular ligand-binding domain of the receptor protein) is widely expressed by different primary human and experimental cancers and can elicit mitogenic responses in the presence of GHRH (10-12). The suppression of the expression of SV1 by antisense RNA-based approache...

show abstract

Section: Discussionmentioning

confidence: 93%

Stimulation of proliferation of MCF-7 breast cancer cells by a transfected splice variant of growth hormone-releasing hormone receptor

Barabutis

Tsellou

Schally

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The inhibitory actions of GHRH antagonists on tumor growth are thought to be mediated by the pituitary type GHRHReceptor and its splice variant-1 (SV-1), which is generated by alternative splicing from the GHRH receptor gene. 6,7 Thus, we have recently reported that human colon cancer cells, in contrast Bcl-2 was diminished after 10 min, followed by an increase in cleaved caspase-9 after 30 min, cleaved caspase-3 after 60 min and finally PARP cleavage, which started to rise 2 hr after addition of JMR-132 to the media.…”

Section: Discussionmentioning

confidence: 94%

“…It has been reported that GHRH antagonists induce apoptosis in LNCap human prostate cancer cells through an elevation in intracellular free Ca 2+ levels. 7 In human endometrial HEC-1A cancer cells, apoptosis induced by GHRH antagonist was followed by an increase in protein expression of the intrinsic and extrinsic pathway of apoptosis. 8 Recent findings, that silencing of p21…”

Section: Introductionmentioning

confidence: 99%

GHRH antagonist causes DNA damage leading to p21 mediated cell cycle arrest and apoptosis in human colon cancer cells

Hohla¹,

Buchholz²,

Seitz³

et al. 2009

Cell Cycle

Self Cite

View full text Add to dashboard Cite

“…Hypothalamic neurohormone GHRH and GHRH-R are not confined to the hypothalamic-pituitary axis, however, but are also produced by various extrahypothalamic sites. GHRH/GHRH-R modulates cell proliferation and apoptosis in many tissues, including prostate (8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

“…In prostate cancer, GHRH antagonist JV-1-38 induces apoptosis in the LNCaP cell model through a calcium-dependent mechanism (11). In models of CRPC, GHRH antagonist JMR-132 suppresses AKT and ERK signaling cascades, thereby decreasing cell proliferation and survival (13).…”

mentioning

confidence: 99%

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer

Fahrenholtz

Rick

García

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Advanced hormone-sensitive prostate cancer responds to androgen-deprivation therapy (ADT); however, therapeutic options for recurrent castration-resistant disease are limited. Because growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) are regulated in an autocrine fashion in prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists-MIA-602, MIA-606, and MIA-690-on the growth of androgen-dependent as well as castration-resistant prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human prostate cancer cell lines. Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R protein compared with castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro, MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of MIA-602. In vivo, MIA-602 was more effective than MIA-606 and MIA-690 and decreased 22Rv1 xenograft tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in body weight occurred. In vitro, the VCaP cell line was minimally inhibited by MIA-602, but in vivo, this line showed a substantial reduction in growth of xenografts in response to MIA-602, indicating both direct and systemic inhibitory effects. MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist MIA-602 for treatment of both androgen-dependent and CRPC.androgen-independent | G protein-coupled receptor | hypothalamic neurohormone | neuropeptide | targeted therapy

show abstract

Antagonist of growth hormone-releasing hormone induces apoptosis in LNCaP human prostate cancer cells through a Ca ²⁺ -dependent pathway

Abstract: growth hormone-releasing hormone antagonist ͉ growth hormone-releasing hormone receptor ͉ calcium ͉ cancer therapy

Cited by 33 publications

References 57 publications

Stimulation of proliferation of MCF-7 breast cancer cells by a transfected splice variant of growth hormone-releasing hormone receptor

Stimulation of proliferation of MCF-7 breast cancer cells by a transfected splice variant of growth hormone-releasing hormone receptor

GHRH antagonist causes DNA damage leading to p21 mediated cell cycle arrest and apoptosis in human colon cancer cells

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer

Contact Info

Product

Resources

About

Antagonist of growth hormone-releasing hormone induces apoptosis in LNCaP human prostate cancer cells through a Ca 2+ -dependent pathway

Abstract: growth hormone-releasing hormone antagonist ͉ growth hormone-releasing hormone receptor ͉ calcium ͉ cancer therapy

Cited by 33 publications

References 57 publications

Stimulation of proliferation of MCF-7 breast cancer cells by a transfected splice variant of growth hormone-releasing hormone receptor

Stimulation of proliferation of MCF-7 breast cancer cells by a transfected splice variant of growth hormone-releasing hormone receptor

GHRH antagonist causes DNA damage leading to p21 mediated cell cycle arrest and apoptosis in human colon cancer cells

Preclinical efficacy of growth hormone-releasing hormone antagonists for androgen-dependent and castration-resistant human prostate cancer

Contact Info

Product

Resources

About

Antagonist of growth hormone-releasing hormone induces apoptosis in LNCaP human prostate cancer cells through a Ca ²⁺ -dependent pathway