Examining the Impact of 4-Nonylphenol on G-361 Malignant Melanoma Cell Proliferation and Apoptosis Activation
Yıl 2025,
Cilt: 36 Sayı: 2, 110 - 114, 27.07.2025
Esra Bilici
,
Cevdet Uğuz
,
Korhan Altunbaş
Öz
Nonylphenol (NP) is among the most prevalent endocrine-disrupting compounds found in the environment. Although the carcinogenic properties of endocrine disruptors have been well investigated, their possible anticancer effects remain comparatively underexplored. This study investigated the cytotoxic and pro-apoptotic effects of NP on G-361 human malignant melanoma cell line. The major objective of the stuyd was to assess anticancer effects of the endocrine-disrupting compound NP on G-361 melanoma cells. The MTT assay was used to determine cell viability, and quantitative real-time PCR was performed to analyze the expression levels of apoptosis-associated genes, including Caspase-3, Bcl-2, Bax, P53, P21, and β-actin. The results indicated a significant decrease in cell viability following treatment with 100 μg/ml NP. Notably, NP exerted a dose-dependent cytotoxic effect, suggesting its possible role in the modulation of apoptotic pathways in melanoma cells. These results require further investigation of different pathways by which NP exerts its effects to gain a deeper insight into its molecular mechanism.
Etik Beyan
Afyon Kocatepe University Animal Experiments Local Ethics Committee gave ethics committee permission for this study with the number 49533702/79 and dated 01/07/2019.
Destekleyen Kurum
This research was supported by Afyon Kocatepe University Scientific Research Projects Coordination Office with the project number “19.SAĞ.BİL.13”.
Proje Numarası
“19.SAĞ.BİL.13”
Teşekkür
This study is derived from publicly defended PhD thesis of the Esra BİLİCİ named author.
Kaynakça
-
Ariemma F, D'Esposito V, Liguoro D et al. (2016). Low-dose bisphenol-a impairs adipogenesis and generates dysfunctional 3t3-l1 adipocytes. PloS one, 11 (3), e0150762.
-
Behari J, Kesari KK (2006). Effects of microwave radiations on reproductive system of male rats. Embryo Talk, 1, 81-85.
-
Bistakowa J, Forgacs Z, Bartos, Zsuzsa et al. (2016). Effects of 4-nonylphenol on the steroidogenesis of human adrenocarcinoma cell line (NCI-H295R). J Environ Sci Heal A, 52 (3), 221–227.
-
Conover WJ (1980). Practical nonparametric statistics. 2nd Edition John Wiley & Sons, 229-239.
-
Cummins DL, Cummins JM, Pantle H et al. (2016). Cutaneous malignant melanoma. Mayo Clin Proc, 81 (4), 500–507.
-
Duan P, Hu C, Butler HJ et al. (2016). Effects of 4-nonylphenol on spermatogenesis and induction of testicular apoptosis through oxidative stress-related pathways. Reprod Toxicol, 62, 27–38.
-
El-Deiry WS (2016). p21(WAF1) Mediates cell-cycle inhibition, relevant to cancer suppression and therapy. Cancer Res, 76 (18), 5189-91.
-
Forte M, Lorenzoa, MD, Carrizzoc A et al. (2016). Nonylphenol effects on human prostate non tumorigenic cells. Toxicology, 16, 21-32.
-
Fridman JS, Lowe SW (2003). Control of apoptosis by p53. Oncogene, 22, 9030–9040.
-
Gałązka A, Jankiewicz U (2022). Endocrine disrupting compounds (nonylphenol and bisphenol a)-sources, harmfulness and laccase-assisted degradation in the aquatic environment. Microorganisms, 10 (11), 2236.
-
Galluzzi L, Chan TA, Kroemer G et al. (2018). The hallmarks of successful anticancer immunotherapy. Sci Transl Med, 10 (459), eaat7807.
-
In SJ, Kim SH, Go RE et al. (2015). Benzophenone-1 and nonylphenol stimulated MCF-7 breast cancer growth by regulating cell cycle and metastasis-related genes via an estrogen receptor α-dependent pathway. J Toxicol Environ Health A, 78 (8), 492–505.
-
Inkaya EN, Tokgöz E, Barlas N. (2025). In vivo investigation of the effects of nonylphenol on the pituitary-adrenal axis and pineal gland in male rats. Basic Clin Pharmacol Toxicol, 136 (3), e70003.
-
Jambor T, Lukáčová J, Tvrdá E et al. (2016). The impact of 4-nonylphenol on the viability and hormone production of mouse leydig cells. Folia Biol (Praha), 62 (1), 34-39.
-
Jambor T, Tvrda E, Tusimova E et al. (2017). In vitro effect of 4-nonylphenol on human chorionic gonadotropin (hCG) stimulated hormone secretion, cell viability and reactive oxygen species generation in mice Leydig cells. Environmental Pollution, 222, 219-225.
-
Kim SH, Nam KH, Hwang KA et al. (2016). Influence of hexabromocyclododecane and 4-nonylphenol on the regulation of cell growth, apoptosis and migration in prostatic cancer cells. Toxicol In Vitro, 32, 240–247.
-
Kong G, Shin KY, Lee JJ (1998). Bcl-2 and p53 expressions in invasive bladder cancers. Acta Oncol, 37, 715-20.
-
Lee JW, Han HK, Park S et al. (2017). Nonylphenol increases tumor formation and growth by suppressing gender-independent lymphocyte proliferation and macrophage activation. Environ Toxicol, 32, 1679-87.
-
Lopez J, Tait SWG (2015). Mitochondrial apoptosis: Killing cancer using the enemy within. Br J Cancer, 112 (6), 957–962.
-
Low IC, Kang J, Pervaız S (2011). Bcl-2: A prime regulator of mitochondrial redox metabolism in cancer cells. Antioxid Redox Signal, 15 (12), 2975-2987.
-
Nakopoulou L, Vourlakou C, Zervas A (1998). The prevalence of bcl-2, p53, and Ki-67 immunoreactivity in transitional cell bladder, carcinomas and their clinicopathologic correlates. Hum Pathol, 29 (2), 146-154.
-
Ogur R (2014). Studies with myrtus communis L.: anticancer properties. J Intercult Ethnopharmacol, 3 (4), 135-137.
-
Park HJ, Zhang M, Lee WY et al. (2020). Toxic effects of nonylphenol on neonatal testicular development in mouse organ culture. Int J Mol Sci, 21 (10), 3491.
-
Park MA, Choi KC (2014). Effects of 4-nonylphenol and bisphenol A on stimulation of cell growth via disruption of the transforming growth factor-β signaling pathway in ovarian cancer models. Chem Res Toxicol, 27 (1), 119–128.
-
Phillips KP, Tanphaichitr N (2008). Human exposure to endocrine disrupters and semen quality. J Toxicol Environ Health B Crit Rev, 11 (3-4), 188–220.
-
Qiu Y, Waters CE, Lewis AE et al. (2002). Oestrogen-induced apoptosis in colonocytes expressing oestrogen receptor beta. J Endocrinol, 174 (3), 369-377.
-
Ruberto S, Santovito A, Simula ER et al. (2022). Bisphenols induce human genomic damage and modulate HERVs/env expression. Environ Mol Mutagen, 63 (6), 275-285.
-
Shariat SF, Kim J, Raptidis G (2003). Association of p53 and p21 expression with clinical outcome in patients with carcinoma in situ of the urinary bladder. Urology, 61 (6), 1140-1145.
-
Shariat SF, Tokunaga H, Zhou J (2004). p53, p21, pRB and p16 expression predict clinical outcome in cystectomy with bladder cancer. J Clin Oncol, 22 (6), 1014-1024.
-
Shi F, Li T, Shi H, Wei Y, Wang J, Liu C, Liang R (2024). Identification of potential therapeutic targets for skin cutaneous melanoma on the basic of transcriptomics. Skin Res Technol, 30 (8), e13916.
-
Soto AM, Justicia H, Wray JW, Sonnenschein C (1991). p-Nonyl-phenol: an estrogenic xenobiotic released from “modified” polystyrene. Environ Health Perspect, 92, 167–173.
-
Thomas S, Quınn BA, Das SK (2013). Targeting the bcl-2 family for cancer therapy. Expert Opin Ther Targets, 17 (1), 61-75.
-
Weert E, Hoekstra-Weebers JE, May AM, Korstjens I, Ros WJ, van der Schans CP (2008). The development of an evidence-based physical self-management rehabilitation programme for cancer survivors. Patient Educ Couns, 71 (2), 169-190.
-
White K, Grether ME, Abrams JM, Young L, Farrell K, Steller H (1994). Genetic control of programmed cell death in Drosophila. Science, 264 (5159), 677-683.
-
Wróblewska-Łuczka P, Góralczyk A, Łuszczki JJ (2023). Synergy, additivity and antagonism between esculetin and six commonly used chemotherapeutics in various malignant melanoma cell lines-an ısobolographic analysis. Molecules, 28 (9), 3889.
-
Xie M, Liang JL, Huang HD et al. (2019). Low doses of nonylphenol promote growth of colon cancer cells through activation of erk1/2 via g protein–coupled receptor 30. Cancer Res Treat, 51 (4), 1620-1631.
-
Yang J, Huang Q, Liu H et al. (2020). 4-Nonylphenol and 4-tert-octylphenol induce anxiety-related behaviors through alternation of 5-HT receptors and transporters in the prefrontal cortex. CompBiochem Physiol C Toxicol Pharmacol, 230, 108701.
-
Yang L, Lin L, Wenga S, et al. (2016). Sexually disrupting effects of nonylphenol and diethylstilbestrol on male silver carp (Carassius auratus) in aquatic microcosms. Ecotoxicol Environ Saf, 71 (2), 400-411.
-
Zeestraten EC, Benard A, Reimers MS et al. (2013). The prognostic value of the apoptosis pathway in colorectal cancer: a review of the literature on biomarkers identified by ımmunohistochemistry. Biomark Cancer, 4 (5), 13-29.
-
Zhang NJ, Zhang Y, Yin S et al. (2022). Nonylphenol promoted epithelial-mesenchymal transition in colorectal cancer cells by upregulating the expression of regulator of cell cycle. Chem Res Toxicol, 35 (9), 1533-1540.
-
Zhu M, Hong D, Bao Y, Wang C, Pan W (2013). Oridonin induces the apoptosis of metastatic hepatocellular carcinoma cells via a mitochondrial pathway. Oncology Letters, 6 (5), 1502-1506.
G-361 Malignant Melanoma Hücrelerinde 4-Nonilfenolün Hücre Proliferasyonu ve Apoptoz Aktivasyonu Üzerindeki Etkisinin Araştırılması
Yıl 2025,
Cilt: 36 Sayı: 2, 110 - 114, 27.07.2025
Esra Bilici
,
Cevdet Uğuz
,
Korhan Altunbaş
Öz
Nonilfenol (NP), çevrede bulunan en yaygın endokrin bozucu bileşikler arasındadır. Endokrin bozucuların kanserojen özellikleri iyi araştırılmış olsa da olası antikanser etkileri nispeten yeterince araştırılmamıştır. Bu çalışma, NP'nin G-361 insan malign melanom hücre hattı üzerindeki sitotoksik ve proapoptotik etkilerini araştırmıştır. Çalışmanın temel amacı, endokrin bozucu bileşik NP'nin G-361 melanom hücreleri üzerindeki antikanser etkilerini değerlendirmekti. Hücre canlılığını belirlemek için MTT testi kullanıldı ve Caspase-3, Bcl-2, Bax, P53, P21 ve β-actin dahil olmak üzere apoptozla ilişkili genlerin ifade düzeylerini analiz etmek için kantitatif gerçek zamanlı PCR gerçekleştirildi. Sonuçlar, 100 μg/ml NP ile tedaviden sonra hücre canlılığında önemli bir azalma olduğunu gösterdi. Özellikle, NP doz bağımlı bir sitotoksik etki gösterdi ve bu da melanom hücrelerinde apoptotik yolların modülasyonunda olası bir rolü olduğunu düşündürdü. Bu sonuçlar, NP'nin moleküler mekanizmasına daha derin bir bakış açısı kazanmak için etkilerini gösterdiği farklı yolların daha fazla araştırılmasını gerektiriyor.
Proje Numarası
“19.SAĞ.BİL.13”
Kaynakça
-
Ariemma F, D'Esposito V, Liguoro D et al. (2016). Low-dose bisphenol-a impairs adipogenesis and generates dysfunctional 3t3-l1 adipocytes. PloS one, 11 (3), e0150762.
-
Behari J, Kesari KK (2006). Effects of microwave radiations on reproductive system of male rats. Embryo Talk, 1, 81-85.
-
Bistakowa J, Forgacs Z, Bartos, Zsuzsa et al. (2016). Effects of 4-nonylphenol on the steroidogenesis of human adrenocarcinoma cell line (NCI-H295R). J Environ Sci Heal A, 52 (3), 221–227.
-
Conover WJ (1980). Practical nonparametric statistics. 2nd Edition John Wiley & Sons, 229-239.
-
Cummins DL, Cummins JM, Pantle H et al. (2016). Cutaneous malignant melanoma. Mayo Clin Proc, 81 (4), 500–507.
-
Duan P, Hu C, Butler HJ et al. (2016). Effects of 4-nonylphenol on spermatogenesis and induction of testicular apoptosis through oxidative stress-related pathways. Reprod Toxicol, 62, 27–38.
-
El-Deiry WS (2016). p21(WAF1) Mediates cell-cycle inhibition, relevant to cancer suppression and therapy. Cancer Res, 76 (18), 5189-91.
-
Forte M, Lorenzoa, MD, Carrizzoc A et al. (2016). Nonylphenol effects on human prostate non tumorigenic cells. Toxicology, 16, 21-32.
-
Fridman JS, Lowe SW (2003). Control of apoptosis by p53. Oncogene, 22, 9030–9040.
-
Gałązka A, Jankiewicz U (2022). Endocrine disrupting compounds (nonylphenol and bisphenol a)-sources, harmfulness and laccase-assisted degradation in the aquatic environment. Microorganisms, 10 (11), 2236.
-
Galluzzi L, Chan TA, Kroemer G et al. (2018). The hallmarks of successful anticancer immunotherapy. Sci Transl Med, 10 (459), eaat7807.
-
In SJ, Kim SH, Go RE et al. (2015). Benzophenone-1 and nonylphenol stimulated MCF-7 breast cancer growth by regulating cell cycle and metastasis-related genes via an estrogen receptor α-dependent pathway. J Toxicol Environ Health A, 78 (8), 492–505.
-
Inkaya EN, Tokgöz E, Barlas N. (2025). In vivo investigation of the effects of nonylphenol on the pituitary-adrenal axis and pineal gland in male rats. Basic Clin Pharmacol Toxicol, 136 (3), e70003.
-
Jambor T, Lukáčová J, Tvrdá E et al. (2016). The impact of 4-nonylphenol on the viability and hormone production of mouse leydig cells. Folia Biol (Praha), 62 (1), 34-39.
-
Jambor T, Tvrda E, Tusimova E et al. (2017). In vitro effect of 4-nonylphenol on human chorionic gonadotropin (hCG) stimulated hormone secretion, cell viability and reactive oxygen species generation in mice Leydig cells. Environmental Pollution, 222, 219-225.
-
Kim SH, Nam KH, Hwang KA et al. (2016). Influence of hexabromocyclododecane and 4-nonylphenol on the regulation of cell growth, apoptosis and migration in prostatic cancer cells. Toxicol In Vitro, 32, 240–247.
-
Kong G, Shin KY, Lee JJ (1998). Bcl-2 and p53 expressions in invasive bladder cancers. Acta Oncol, 37, 715-20.
-
Lee JW, Han HK, Park S et al. (2017). Nonylphenol increases tumor formation and growth by suppressing gender-independent lymphocyte proliferation and macrophage activation. Environ Toxicol, 32, 1679-87.
-
Lopez J, Tait SWG (2015). Mitochondrial apoptosis: Killing cancer using the enemy within. Br J Cancer, 112 (6), 957–962.
-
Low IC, Kang J, Pervaız S (2011). Bcl-2: A prime regulator of mitochondrial redox metabolism in cancer cells. Antioxid Redox Signal, 15 (12), 2975-2987.
-
Nakopoulou L, Vourlakou C, Zervas A (1998). The prevalence of bcl-2, p53, and Ki-67 immunoreactivity in transitional cell bladder, carcinomas and their clinicopathologic correlates. Hum Pathol, 29 (2), 146-154.
-
Ogur R (2014). Studies with myrtus communis L.: anticancer properties. J Intercult Ethnopharmacol, 3 (4), 135-137.
-
Park HJ, Zhang M, Lee WY et al. (2020). Toxic effects of nonylphenol on neonatal testicular development in mouse organ culture. Int J Mol Sci, 21 (10), 3491.
-
Park MA, Choi KC (2014). Effects of 4-nonylphenol and bisphenol A on stimulation of cell growth via disruption of the transforming growth factor-β signaling pathway in ovarian cancer models. Chem Res Toxicol, 27 (1), 119–128.
-
Phillips KP, Tanphaichitr N (2008). Human exposure to endocrine disrupters and semen quality. J Toxicol Environ Health B Crit Rev, 11 (3-4), 188–220.
-
Qiu Y, Waters CE, Lewis AE et al. (2002). Oestrogen-induced apoptosis in colonocytes expressing oestrogen receptor beta. J Endocrinol, 174 (3), 369-377.
-
Ruberto S, Santovito A, Simula ER et al. (2022). Bisphenols induce human genomic damage and modulate HERVs/env expression. Environ Mol Mutagen, 63 (6), 275-285.
-
Shariat SF, Kim J, Raptidis G (2003). Association of p53 and p21 expression with clinical outcome in patients with carcinoma in situ of the urinary bladder. Urology, 61 (6), 1140-1145.
-
Shariat SF, Tokunaga H, Zhou J (2004). p53, p21, pRB and p16 expression predict clinical outcome in cystectomy with bladder cancer. J Clin Oncol, 22 (6), 1014-1024.
-
Shi F, Li T, Shi H, Wei Y, Wang J, Liu C, Liang R (2024). Identification of potential therapeutic targets for skin cutaneous melanoma on the basic of transcriptomics. Skin Res Technol, 30 (8), e13916.
-
Soto AM, Justicia H, Wray JW, Sonnenschein C (1991). p-Nonyl-phenol: an estrogenic xenobiotic released from “modified” polystyrene. Environ Health Perspect, 92, 167–173.
-
Thomas S, Quınn BA, Das SK (2013). Targeting the bcl-2 family for cancer therapy. Expert Opin Ther Targets, 17 (1), 61-75.
-
Weert E, Hoekstra-Weebers JE, May AM, Korstjens I, Ros WJ, van der Schans CP (2008). The development of an evidence-based physical self-management rehabilitation programme for cancer survivors. Patient Educ Couns, 71 (2), 169-190.
-
White K, Grether ME, Abrams JM, Young L, Farrell K, Steller H (1994). Genetic control of programmed cell death in Drosophila. Science, 264 (5159), 677-683.
-
Wróblewska-Łuczka P, Góralczyk A, Łuszczki JJ (2023). Synergy, additivity and antagonism between esculetin and six commonly used chemotherapeutics in various malignant melanoma cell lines-an ısobolographic analysis. Molecules, 28 (9), 3889.
-
Xie M, Liang JL, Huang HD et al. (2019). Low doses of nonylphenol promote growth of colon cancer cells through activation of erk1/2 via g protein–coupled receptor 30. Cancer Res Treat, 51 (4), 1620-1631.
-
Yang J, Huang Q, Liu H et al. (2020). 4-Nonylphenol and 4-tert-octylphenol induce anxiety-related behaviors through alternation of 5-HT receptors and transporters in the prefrontal cortex. CompBiochem Physiol C Toxicol Pharmacol, 230, 108701.
-
Yang L, Lin L, Wenga S, et al. (2016). Sexually disrupting effects of nonylphenol and diethylstilbestrol on male silver carp (Carassius auratus) in aquatic microcosms. Ecotoxicol Environ Saf, 71 (2), 400-411.
-
Zeestraten EC, Benard A, Reimers MS et al. (2013). The prognostic value of the apoptosis pathway in colorectal cancer: a review of the literature on biomarkers identified by ımmunohistochemistry. Biomark Cancer, 4 (5), 13-29.
-
Zhang NJ, Zhang Y, Yin S et al. (2022). Nonylphenol promoted epithelial-mesenchymal transition in colorectal cancer cells by upregulating the expression of regulator of cell cycle. Chem Res Toxicol, 35 (9), 1533-1540.
-
Zhu M, Hong D, Bao Y, Wang C, Pan W (2013). Oridonin induces the apoptosis of metastatic hepatocellular carcinoma cells via a mitochondrial pathway. Oncology Letters, 6 (5), 1502-1506.