Goserelin promotes the apoptosis of epithelial ovarian cancer cells by upregulating forkhead boxï¿½O1 through the PI3K/AKT signaling pathway

Zhang, Ning; Zheng, Tingting; Zhang, Xiaodan; Hua, Keqin; Zhang, Ying

doi:10.3892/or.2017.6159

Cited by 9 publications

(10 citation statements)

References 31 publications

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“…These results indicated that the conjugates containing acylated Lys in position 4 exerted their cytotoxic effect, at least in part, via a PI3K-dependent mechanism, while the PI3K seemed to be not involved in the cytotoxicity of the parent conjugate (GnRH-III(Dau=Aoa)). These results are in good agreement with previous studies about the involvement of PI3K signaling pathway in the pro-apoptotic effects of GnRH analogs on prostate [ 41 ] and ovarian [ 42 ] cancer cells as well as in the chemotaxis of leukemic cells [ 43 ] induced by GnRH-III derivatives.…”

Section: Resultssupporting

confidence: 92%

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

Lajkó

Spring

Hegedüs

et al. 2018

Beilstein J. Org. Chem.

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Background: Peptide hormone-based targeted tumor therapy is an approved strategy to selectively block the tumor growth and spreading. The gonadotropin-releasing hormone receptors (GnRH-R) overexpressed on different tumors (e.g., melanoma) could be utilized for drug-targeting by application of a GnRH analog as a carrier to deliver a covalently linked chemotherapeutic drug directly to the tumor cells. In this study our aim was (i) to analyze the effects of GnRH-drug conjugates on melanoma cell proliferation, adhesion and migration, (ii) to study the mechanisms of tumor cell responses, and (iii) to compare the activities of conjugates with the free drug. Results: In the tested conjugates, daunorubicin (Dau) was coupled to 8Lys of GnRH-III (GnRH-III(Dau=Aoa)) or its derivatives modified with 4Lys acylated with short-chain fatty acids (acetyl group in [4Lys(Ac)]-GnRH-III(Dau=Aoa) and butyryl group in [4Lys(Bu)]-GnRH-III(Dau=Aoa)). The uptake of conjugates by A2058 melanoma model cells proved to be time dependent. Impedance-based proliferation measurements with xCELLigence SP system showed that all conjugates elicited irreversible tumor growth inhibitory effects mediated via a phosphoinositide 3-kinase-dependent signaling. GnRH-III(Dau=Aoa) and [4Lys(Ac)]-GnRH-III(Dau=Aoa) were shown to be blockers of the cell cycle in the G2/M phase, while [4Lys(Bu)]-GnRH-III(Dau=Aoa) rather induced apoptosis. In short-term, the melanoma cell adhesion was significantly increased by all the tested conjugates. The modification of the GnRH-III in position 4 was accompanied by an increased cellular uptake, higher cytotoxic and cell adhesion inducer activity. By studying the cell movement of A2058 cells with a holographic microscope, it was found that the migratory behavior of melanoma cells was increased by [4Lys(Ac)]-GnRH-III(Dau=Aoa), while the GnRH-III(Dau=Aoa) and [4Lys(Bu)]-GnRH-III(Dau=Aoa) decreased this activity. Conclusion: Internalization and cytotoxicity of the conjugates showed that GnRH-III peptides could guard Dau to melanoma cells and promote antitumor activity. [4Lys(Bu)]-GnRH-III(Dau=Aoa) possessing the butyryl side chain acting as a “second drug” proved to be the best candidate for targeted tumor therapy due to its cytotoxicity and immobilizing effect on tumor cell spreading. The applicability of impedimetry and holographic phase imaging for characterizing cancer cell behavior and effects of targeted chemotherapeutics with small structural differences (e.g., length of the side chain in 4Lys) was also clearly suggested.

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Section: Resultssupporting

confidence: 92%

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

Lajkó

Spring

Hegedüs

et al. 2018

Beilstein J. Org. Chem.

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“…In the case of ovarian carcinoma and multiple myeloma cells, the enhancement of TP53 expression was also demonstrated against the background of the antitumor effect of different GnRH-I agonists and antagonists [30,55]. Zhang and his coworkers have recently reported that goserelin induced apoptosis in epithelial ovarian cancer cells by partly upregulating factors of the TNF and TNF-receptor superfamilies [29]. Several studies have demonstrated that treatment with a GnRH-I analog could induce FASL expression in different reproductive cancer cells [55,56].…”

Section: Discussionmentioning

confidence: 99%

“…Depending on the cell type and GnRH analog, the extent of the apoptosis and its underlying pathways prove to be different. Goserelin, a GnRH-I agonist, has been demonstrated to increase the expression of the proapoptotic protein B-cell CLL/lymphoma 2 (BCL2)-associated X protein (BAX) in a TP53-dependent manner in a prostate cancer cell line [28], while in the case of ovarian cell lines, this analog could upregulate several members of tumor necrosis factor (TNF) and TNF-receptor superfamilies through the Forkhead Box O1–Phosphoinositide-3-Kinase–v-akt murine thymoma viral oncogene homolog (AKT) pathway [29]. The induction of anti-oncogenes was also shown to contribute to the apoptosis of multiple myeloma cells induced by the GnRH-I agonist [30].…”

Section: Introductionmentioning

confidence: 99%

“…In most of the above-mentioned molecular biological studies on apoptosis, only GnRH-I analogs (e.g., goserelin) and conjugates (e.g., zoptarelin doxorubicin) were thoroughly investigated [26,29,30,36]. Nevertheless, the conjugates of GnRH-II and GnRH-III proved to have a comparable antitumor effect; moreover, they have been indicated to possess higher tumor selectivity and stability than that the GnRH-I-based conjugate [12,21,37,38].…”

Section: Introductionmentioning

confidence: 99%

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Apoptotic Effects of Drug Targeting Conjugates Containing Different GnRH Analogs on Colon Carcinoma Cells

Lajkó

Hegedüs

Mező

et al. 2019

IJMS

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The wide range of cellular target reactions (e.g., antitumor) of gonadotropin-releasing hormone (GnRH) variants provides the possibility to develop multifunctional GnRH conjugates. The aim of our work was to compare the cytotoxic/apoptotic activity of different GnRH-based, daunorubicin (Dau)-linked conjugates with or without butyrated Lys in position 4 (4Lys(Bu)) at a molecular level in a human colorectal carcinoma cell line. Cell viability was measured by impedimetry, cellular uptake and apoptosis were studied by flow cytometry, and the expression of apoptosis-related genes was analyzed by qRT-PCR. The modification with 4Lys(Bu) resulted in an increased cytotoxic and apoptotic effects and cellular uptake of the GnRH-I and GnRH-III conjugates. Depending on the GnRH isoform and the presence of 4Lys(Bu), the conjugates could regulate the expression of several apoptosis-related genes, especially tumor necrosis factor (TNF), tumor protein p53 (TP53) and the members of growth-factor signaling. The stronger cytotoxicity of GnRH-I and GnRH-III conjugates containing 4Lys(Bu) was associated with a stronger inhibitory effect on the expression of growth-factor signaling elements in comparison with their 4Ser counterparts, in which the upregulation of TP53 and caspases (e.g., CASP9) seemed to play a more important role. We were able to provide further evidence that targeting the GnRH receptor could serve as a successful therapeutic approach in colon cancer, and GnRH-III-[4Lys(Bu),8Lys(Dau=Aoa)] proved to be the best candidate for this purpose.

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“…FoxO belongs to the forkhead box transcriptional protein O subfamily and is considered necessary to maintain spermatogonial stem cell homeostasis and spermatogenesis (Goertz, Wu, Gallardo, Hamra, & Castrillon, ). The main upstream signalling pathways regulating FoxO are PI3K, AMPK and ERKI/2 (Goertz et al, ; Kim et al, ; Pan et al, ; Zhang et al, ). The TGF‐β signalling pathway plays a key role in regulation of the proliferation, differentiation and apoptosis of most cells.…”

Section: Discussionmentioning

confidence: 99%

Photoperiodic effect on the testicular transcriptome in broiler roosters

Sun

Wang

et al. 2020

Animal Physiology Nutrition

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Information about the effects of photoperiod on the testicular transcriptome of broiler roosters is limited. The aim of the present study was to explore the effect of different photoperiodic regimes on gene expression in the testes of broiler breeder roosters. One hundred and twenty Arbor Acres broiler breeder roosters aged 20 weeks were assigned to one of three groups (n = 40) and subjected to different photoperiodic regimes: control (CTR; 12.5 L:11.5 D), short day (SD; 8 L:16 D) and long day (LD; 16 L:8 D). After 4 weeks, the testes of 10 randomly selected birds from each group were dissected, sliced and haematoxylin-eosin stained. The testicular transcriptome of roosters from the SD and LD groups was determined by RNA sequencing (RNA-Seq), and the results were confirmed using quantitative real-time PCR. The seminiferous tubule area and sperm count increased significantly with the prolongation of photoperiod (p < .01). Additionally, the RNA-Seq results indicated that 387 genes were upregulated and 1,052 genes were downregulated in the LD group compared with those in the SD group. Several crucial genes involved in rooster testicular development and reproduction were also screened, including heat shock proteins 90, extracellular regulated protein kinases 1, phosphatidylinositol 3-kinase, adenosine 5'-monophosphate -activated protein kinase, BCL-6 and Smad3. The differentially expressed genes were enriched in the mammalian targets of rapamycin (mTOR), forkhead box (FoxO), transforming growth factor beta (TGF-β) and insulin signalling pathway. In conclusion, a 16 hr photoperiod for 4 weeks increased the seminiferous tubule duct area and promoted spermatogenesis in the rooster's testicles, and the mTOR, FoxO, TGF-β and insulin signalling pathways may be involved. K E Y W O R D S photoperiod, RNA-seq, rooster, testicular development S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Sun L, Guo L, Wang J, et al. Photoperiodic effect on the testicular transcriptome in broiler roosters.

show abstract

Goserelin promotes the apoptosis of epithelial ovarian cancer cells by upregulating forkhead boxï¿½O1 through the PI3K/AKT signaling pathway

Cited by 9 publications

References 31 publications

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

Comparative cell biological study of in vitro antitumor and antimetastatic activity on melanoma cells of GnRH-III-containing conjugates modified with short-chain fatty acids

Apoptotic Effects of Drug Targeting Conjugates Containing Different GnRH Analogs on Colon Carcinoma Cells

Photoperiodic effect on the testicular transcriptome in broiler roosters

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