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

Hohla, Florian; Buchholz, Stefan; Seitz, Stefan; Rick, Ferenc G.; Szalontay, Luca; Varga, József; Zarándi, Márta; Halmos, Gábor; Vidaurre, Irving; Krishan, Awtar; Kurtoğlu, Metin; Chandna, Sudhir; Aigner, Elmar; Datz, Christian

doi:10.4161/cc.8.19.9698

Cited by 37 publications

(37 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our observation of the transcriptional suppression of Cdkn1a/p21 and Cdkn2a/p16, factors involved in cell-cycle control and DNA damage repair, in PC-3 tumors after treatment with the GHRH antagonist JMR-132 are in line with our recent findings (17). The mRNA levels of the proapoptotic genes Bad and Bax were up-regulated, whereas the expression of antiapoptotic Bcl2 was lowered significantly, confirming our recent observations (28,47). We found that transcriptional levels of signal transduction molecules and transcription factors Akt1, Erbb2, Fas, and Nfkb1 were down-regulated after treatment with JMR-132.…”

Section: Discussionsupporting

confidence: 82%

Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases

Rick

Schally

Szalontay

et al. 2012

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

Self Cite

View full text Add to dashboard Cite

The management of castration-resistant prostate cancer (CRPC) presents a clinical challenge because of limitations in efficacy of current therapies. Novel therapeutic strategies for the treatment of CRPC are needed. Antagonists of hypothalamic growth hormone-releasing hormone (GHRH) inhibit growth of various malignancies, including androgen-dependent and independent prostate cancer, by suppressing diverse tumoral growth factors, especially GHRH itself, which acts as a potent autocrine/paracrine growth factor in many tumors. We evaluated the effects of the GHRH antagonist, JMR-132, on PC-3 human androgen-independent prostate cancer cells in vitro and in vivo. JMR-132 suppressed the proliferation of PC-3 cells in vitro in a dose-dependent manner and significantly inhibited growth of PC-3 tumors by 61% ( P < 0.05). The expression of GHRH, GHRH receptors, and their main splice variant, SV1, in PC-3 cells and tumor xenografts was demonstrated by RT-PCR and Western blot. The content of GHRH protein in PC-3 xenografts was lowered markedly, by 66.3% ( P < 0.01), after treatment with JMR-132. GHRH induced a significant increase in levels of ERK, but JMR-132 abolished this outcome. Our findings indicate that inhibition of PC-3 prostate cancer by JMR-132 involves inactivation of Akt and ERK. The inhibitory effect produced by GHRH antagonist can result in part from inactivation of the PI3K/Akt/mammalian target of rapamycin and Raf/MEK/ERK pathways and from the reduction in GHRH produced by cancer cells. Our findings support the role of GHRH as an autocrine growth factor in prostate cancer and suggest that antagonists of GHRH should be considered for further development as therapy for CRPC.

show abstract

Section: Discussionsupporting

confidence: 82%

Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases

Rick

Schally

Szalontay

et al. 2012

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Beyond these canonical pathways, accumulating evidence indicates that additional intracellular molecules and pathways can be modulated by GHRH-R antagonists. JMR-132 induced cell-growth inhibition and apoptosis through PKCδ-mediated activation of p53/p21 in endometrial cancer (39) and caused p21-mediated S-phase arrest in colon cancer (40). Another GHRH-R antagonist, MZ-J-7-138, up-regulated wild-type p53 but down-regulated mutant p53 and p21 in prostate cancer (41).…”

Section: Discussionmentioning

confidence: 99%

Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1–STAT3/NF-κB signaling

Gan

Jiang

et al. 2016

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

View full text Add to dashboard Cite

Gastric cancer (GC) ranks as the fourth most frequent in incidence and second in mortality among all cancers worldwide. The development of effective treatment approaches is an urgent requirement. Growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) have been found to be present in a variety of tumoral tissues and cell lines. Therefore the inhibition of GHRH-R was proposed as a promising approach for the treatment of these cancers. However, little is known about GHRH-R and the relevant therapy in human GC. By survival analyses of multiple cohorts of GC patients, we identified that increased GHRH-R in tumor specimens correlates with poor survival and is an independent predictor of patient prognosis. We next showed that MIA-602, a highly potent GHRH-R antagonist, effectively inhibited GC growth in cultured cells. Further, this inhibitory effect was verified in multiple models of human GC cell lines xenografted into nude mice. Mechanistically, GHRH-R antagonists target GHRH-R and down-regulate the p21-activated kinase 1 (PAK1)-mediated signal transducer and activator of transcription 3 (STAT3)/nuclear factor-κB (NF-κB) inflammatory pathway. Overall, our studies establish GHRH-R as a potential molecular target in human GC and suggest treatment with GHRH-R antagonist as a promising therapeutic intervention for this cancer.GHRH receptor | GHRH-R antagonist | PAK1 | stomach cancer | prognostic predictor

show abstract

“…Recently, we studied the signal transduction in glioblastoma cell lines following treatment with a GHRH antagonist and found that it affects cell death through the key pro-apoptotic pathways: the reduction of phosphorylated Akt, GSK3β and p44/42 MAPK, the cleavage of PARP and caspase-3 as well as through the intracellular translocation of proteins AIF, EndoG and cyt c (22). Our group also demonstrated that antagonism of GHRH abolishes the integrity of the mitochondrial membrane, thus promoting apoptosis (22,41). In the present study we investigated the level of phosphorylation of Akt, GSK3β and p44/42 MAPK following exposure to a novel GHRH antagonist, MIA-602, in nine different breast cancer cell lines.…”

Section: Discussionmentioning

confidence: 99%

The effect of a novel antagonist of growth hormone releasing hormone on cell proliferation and on the key cell signaling pathways in nine different breast cancer cell lines

et al. 2011

View full text Add to dashboard Cite

Abstract. Growth hormone releasing hormone (GHRH) antagonists have been developed for the treatment of various cancers. We investigated the effects of a novel GHRH antagonist, MIA-602, on nine breast cancer cell lines, differing in their expression for estrogen-, progesterone-and HER-2 receptors. We detected the presence of pituitary-type GHRH receptors (pGHRH-R) on 6 of the 9 breast cancer cell lines. The main splice variant of pGHRH-R, SV1, was found on all 9 cell lines. MTT assay showed that following treatment with MIA-602, cell viability decreased significantly in all 9 cell lines. The reduction in cell viability was greater in cells positive for both pGHRH-R and SV1, than in cells positive for only SV1, but the difference was not significant. Using Western blotting, we demonstrated that the levels of phosphoAkt, -GSK3β and -ERK1/2 decreased significantly following exposure to MIA-602 and the level of phospho-p38 increased after treatment. The reduction of the phosphorylated antiapoptotic proteins was significantly greater in cells where both pGHRH-R and SV1 were present, than where only SV1 was expressed. In conclusion, our study shows that MIA-602 is effective against a wide range of breast cancer cells in vitro, independently of their receptor positivity, suggesting the potential use of GHRH antagonists also in the treatment of triple-negative breast cancer. The effect of MIA-602 was mediated nearly as well in tumors that expressed only the SV1 receptor compared to those in which both SV1 and pGHRH-R were present, although a difference could be detected at the level of cell signaling.

show abstract

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

Cited by 37 publications

References 22 publications

Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases

Antagonists of growth hormone-releasing hormone inhibit growth of androgen-independent prostate cancer through inactivation of ERK and Akt kinases

Growth hormone-releasing hormone receptor antagonists inhibit human gastric cancer through downregulation of PAK1–STAT3/NF-κB signaling

The effect of a novel antagonist of growth hormone releasing hormone on cell proliferation and on the key cell signaling pathways in nine different breast cancer cell lines

Contact Info

Product

Resources

About