Ethanol extract of Patrinia scabiosaefolia induces the death of human renal cell carcinoma 786-O cells via SIRT-1 and mTOR signaling-mediated metabolic disruptions

Li,Zeyan; Tang,Yueqing; Zhu,Shiqin; Li,Dawei; Han,Xiao; Gu,Gangli; Xing,Naidong; Ren,Juchao; Guo,Zhaoxin; Jiao,Wei; Yan,Lei; Xu,Zhonghua; Zhang,Wenhua

doi:10.3892/or.2017.6139

Ethanol extract of Patrinia scabiosaefolia induces the death of human renal cell carcinoma 786-O cells via SIRT-1 and mTOR signaling-mediated metabolic disruptions

Authors:
- Zeyan Li
- Yueqing Tang
- Shiqin Zhu
- Dawei Li
- Xiao Han
- Gangli Gu
- Naidong Xing
- Juchao Ren
- Zhaoxin Guo
- Wei Jiao
- Lei Yan
- Zhonghua Xu
- Wenhua Zhang
View Affiliations

Affiliations: Department of Urology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China, Department of Biochemistry, Shandong University, Jinan, Shandong 250012, P.R. China
Published online on: December 7, 2017 https://doi.org/10.3892/or.2017.6139
Pages: 764-772

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Recently, natural plant extracts have shown tremendous potential as novel antitumor drugs. Patrinia scabiosaefolia, a traditional prescription for inflammatory diseases, has been reported to effectively suppress various types of cancers. However, the mechanisms underlying its antitumor properties remain elusive. In the present study, we investigated the antitumor effects of an ethanol extract of Patrinia scabiosaefolia (EPS) on human renal cell carcinoma 786-O cells. After 24 h of incubation with EPS, the cell viability and colony number of 786-O cells were significantly decreased in a concentration-dependent manner as compared to the control group as determined by MTT and colony formation assays, respectively. The necrotic rate and apoptotic rate in the EPS exposure group were significantly higher than these rates noted in the control group as revealed by LDH release assay and Hoechst 33342/ PI double staining, respectively. At the concentration of 1.0 mg/ml, the necrotic and apoptotic rates reached 41.7±6.6 and 7.8±1.4%, respectively (P<0.01). However, the fluorescence intensity of intracellular calcium concentration ([Ca2+]i) was markedly elevated from 0.029±0.0007 to 0.060±0.003 (P<0.001) after the intervention of EPS. Moreover, the fluorescence intensity of intracellular ROS in the EPS exposure group was significantly higher (0.074±0.005) compared to that observed in the control group (0.033±0.001, P<0.001), which was partly attenuated by the specific antioxidant N-acetylcysteine (NAC). Furthermore, our results demonstrated that EPS significantly downregulated the expression of SIRT-1 and obviously induced the dephosphorylation of mTOR. Moreover, combined treatment with the SIRT-1 inhibitor nicotinamide and EPS was able to significantly enhance the induction of necrosis and reduction in cell viability of 786-O cells noted following treatment with EPS alone. In summary, we conclude that EPS induced the death of 786-O cells via SIRT-1 and mTOR signaling-mediated metabolic disruptions, which provide novel insight into the application of natural plant extracts for the treatment of cancers.

View Figures

View References

1	Kan XX, Li Q, Chen X, Wang YJ, Li YJ, Yang Q, Xiao HB, Wang ZX, Chen Y, Weng XG, et al: A novel cell cycle blocker extracted from Stellera chamaejasme L. inhibits the proliferation of hepatocarcinoma cells. Oncol Rep. 35:3480–3488. 2016. View Article : Google Scholar : PubMed/NCBI
2	Gordaliza M: Natural products as leads to anticancer drugs. Clin Transl Oncol. 9:767–776. 2007. View Article : Google Scholar : PubMed/NCBI
3	Brglez Mojzer E, Knez Hrnčič M, Škerget M, Knez Ž and Bren U: Polyphenols: Extraction methods, antioxidative action, bioavailability and anticarcinogenic effects. Molecules. 21:212016. View Article : Google Scholar
4	Lin J, Cai QY, Xu W, Lin JM and Peng J: Chemical composition, anticancer, anti-neuroinflammatory, and antioxidant activities of the essential oil of Patrinia scabiosaefolia. Chin J Integr Med. Sep 1–2016.(Epub ahead of print). View Article : Google Scholar
5	Cho EJ, Shin JS, Noh YS, Cho YW, Hong SJ, Park JH, Lee JY, Lee JY and Lee KT: Anti-inflammatory effects of methanol extract of Patrinia scabiosaefolia in mice with ulcerative colitis. J Ethnopharmacol. 136:428–435. 2011. View Article : Google Scholar : PubMed/NCBI
6	Zhang M, Sun G, Shen A, Liu L, Ding J and Peng J: Patrinia scabiosaefolia inhibits the proliferation of colorectal cancer in vitro and in vivo via G1/S cell cycle arrest. Oncol Rep. 33:856–860. 2015. View Article : Google Scholar : PubMed/NCBI
7	Ju HK, Baek SH, An RB, Bae K, Son KH, Kim HP, Kang SS, Lee SH, Son JK and Chang HW: Inhibitory effects of nardostachin on nitric oxide, prostaglandin E2, and tumor necrosis factor-α production in lipopolysaccharide activated macrophages. Biol Pharm Bull. 26:1375–1378. 2003. View Article : Google Scholar : PubMed/NCBI
8	Chen L, Liu L, Ye L, Shen A, Chen Y, Sferra TJ and Peng J: Patrinia scabiosaefolia inhibits colorectal cancer growth through suppression of tumor angiogenesis. Oncol Rep. 30:1439–1443. 2013. View Article : Google Scholar : PubMed/NCBI
9	Peng J, Chen Y, Lin J, Zhuang Q, Xu W, Hong Z and Sferra TJ: Patrinia scabiosaefolia extract suppresses proliferation and promotes apoptosis by inhibiting the STAT3 pathway in human multiple myeloma cells. Mol Med Rep. 4:313–318. 2011.PubMed/NCBI
10	Chiu LC, Ho TS, Wong EY and Ooi VE: Ethyl acetate extract of Patrinia scabiosaefolia downregulates anti-apoptotic Bcl-2/Bcl-XL expression, and induces apoptosis in human breast carcinoma MCF-7 cells independent of caspase-9 activation. J Ethnopharmacol. 105:263–268. 2006. View Article : Google Scholar : PubMed/NCBI
11	Schulze A and Harris AL: How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature. 491:364–373. 2012. View Article : Google Scholar : PubMed/NCBI
12	Trachootham D, Alexandre J and Huang P: Targeting cancer cells by ROS-mediated mechanisms: A radical therapeutic approach? Nat Rev Drug Discov. 8:579–591. 2009. View Article : Google Scholar : PubMed/NCBI
13	Panieri E and Santoro MM: ROS homeostasis and metabolism: A dangerous liason in cancer cells. Cell Death Dis. 7:e22532016. View Article : Google Scholar : PubMed/NCBI
14	Yan Y, Wei CL, Zhang WR, Cheng HP and Liu J: Cross-talk between calcium and reactive oxygen species signaling. Acta Pharmacol Sin. 27:821–826. 2006. View Article : Google Scholar : PubMed/NCBI
15	Ganie SA, Dar TA, Bhat AH, Dar KB, Anees S, Zargar MA and Masood A: Melatonin: A potential anti-oxidant therapeutic agent for mitochondrial dysfunctions and related disorders. Rejuvenation Res. 19:21–40. 2016. View Article : Google Scholar : PubMed/NCBI
16	Li Z, Wang H, Wang Q and Sun J: Buyang Huanwu decoction vigorously rescues PC12 cells against 6-OHDA-induced neurotoxicity via Akt/GSK3β pathway based on serum pharmacology methodology. Rejuvenation Res. 19:467–477. 2016. View Article : Google Scholar : PubMed/NCBI
17	Ghosh HS, McBurney M and Robbins PD: SIRT1 negatively regulates the mammalian target of rapamycin. PLoS One. 5:e91992010. View Article : Google Scholar : PubMed/NCBI
18	Zhang ZY, Hong D, Nam SH, Kim JM, Paik YH, Joh JW, Kwon CH, Park JB, Choi GS, Jang KY, et al: SIRT1 regulates oncogenesis via a mutant p53-dependent pathway in hepatocellular carcinoma. J Hepatol. 62:121–130. 2015. View Article : Google Scholar : PubMed/NCBI
19	Liu Z, Gu H, Gan L, Xu Y, Feng F, Saeed M and Sun C: Reducing Smad3/ATF4 was essential for Sirt1 inhibiting ER stress-induced apoptosis in mice brown adipose tissue. Oncotarget. 8:9267–9279. 2017.PubMed/NCBI
20	Jang KY, Hwang SH, Kwon KS, Kim KR, Choi HN, Lee NR, Kwak JY, Park BH, Park HS, Chung MJ, et al: SIRT1 expression is associated with poor prognosis of diffuse large B-cell lymphoma. Am J Surg Pathol. 32:1523–1531. 2008. View Article : Google Scholar : PubMed/NCBI
21	Chen HC, Jeng YM, Yuan RH, Hsu HC and Chen YL: SIRT1 promotes tumorigenesis and resistance to chemotherapy in hepatocellular carcinoma and its expression predicts poor prognosis. Ann Surg Oncol. 19:2011–2019. 2012. View Article : Google Scholar : PubMed/NCBI
22	Lee H, Kim KR, Noh SJ, Park HS, Kwon KS, Park BH, Jung SH, Youn HJ, Lee BK, Chung MJ, et al: Expression of DBC1 and SIRT1 is associated with poor prognosis for breast carcinoma. Hum Pathol. 42:204–213. 2011. View Article : Google Scholar : PubMed/NCBI
23	Dibble CC and Cantley LC: Regulation of mTORC1 by PI3K signaling. Trends Cell Biol. 25:545–555. 2015. View Article : Google Scholar : PubMed/NCBI
24	Zoncu R, Efeyan A and Sabatini DM: mTOR: From growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 12:21–35. 2011. View Article : Google Scholar : PubMed/NCBI
25	Menendez JA and Lupu R: Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 7:763–777. 2007. View Article : Google Scholar : PubMed/NCBI
26	Liu L, Shen A, Chen Y, Wei L, Lin J, Sferra TJ, Hong Z and Peng J: Patrinia scabiosaefolia induces mitochondrial-dependent apoptosis in a mouse model of colorectal cancer. Oncol Rep. 30:897–903. 2013. View Article : Google Scholar : PubMed/NCBI
27	Cairns RA, Harris IS and Mak TW: Regulation of cancer cell metabolism. Nat Rev Cancer. 11:85–95. 2011. View Article : Google Scholar : PubMed/NCBI
28	Liu X, Yang T, Sun T and Shao K: SIRT1mediated regulation of oxidative stress induced by Pseudomonas aeruginosa lipopolysaccharides in human alveolar epithelial cells. Mol Med Rep. 15:813–818. 2017. View Article : Google Scholar : PubMed/NCBI
29	Li B, He X, Zhuang M, Niu B, Wu C, Mu H, Tang F, Cui Y, Liu W, Zhao B, et al: Melatonin ameliorates busulfan-induced spermatogonial stem cell oxidative apoptosis in mouse testes. Antioxid Redox Signal. Jan. 27–2017.(Epub ahead of print). View Article : Google Scholar :
30	Park EY, Woo Y, Kim SJ, Kim DH, Lee EK, De U, Kim KS, Lee J, Jung JH, Ha KT, et al: Anticancer effects of a new SIRT inhibitor, MHY2256, against human breast cancer MCF-7 cells via regulation of MDM2-p53 binding. Int J Biol Sci. 12:1555–1567. 2016. View Article : Google Scholar : PubMed/NCBI
31	Zhang S, Huang S, Deng C, Cao Y, Yang J, Chen G, Zhang B, Duan C, Shi J, Kong B, et al: Co-ordinated overexpression of SIRT1 and STAT3 is associated with poor survival outcome in gastric cancer patients. Oncotarget. 8:18848–18860. 2017.PubMed/NCBI
32	Jang KY, Kim KS, Hwang SH, Kwon KS, Kim KR, Park HS, Park BH, Chung MJ, Kang MJ, Lee DG, et al: Expression and prognostic significance of SIRT1 in ovarian epithelial tumours. Pathology. 41:366–371. 2009. View Article : Google Scholar : PubMed/NCBI
33	Kim I, Rodriguez-Enriquez S and Lemasters JJ: Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys. 462:245–253. 2007. View Article : Google Scholar : PubMed/NCBI
34	Brachmann SM, Hofmann I, Schnell C, Fritsch C, Wee S, Lane H, Wang S, Garcia-Echeverria C and Maira SM: Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc Natl Acad Sci USA. 106:pp. 22299–22304. 2009; View Article : Google Scholar : PubMed/NCBI
35	Chen J, Yuan J, Zhou L, Zhu M, Shi Z, Song J, Xu Q, Yin G, Lv Y, Luo Y, et al: Regulation of different components from Ophiopogon japonicus on autophagy in human lung adenocarcinoma A549 cells through PI3K/Akt/mTOR signaling pathway. Biomed Pharmacother. 87:118–126. 2017. View Article : Google Scholar : PubMed/NCBI
36	Lin F, Lei S, Ma J, et al: [Inhibitory effect of jianpi-jiedu prescription-contained serum on colorectal cancer SW48 cell proliferation by mTOR-P53-P21 signalling pathway]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 41:1128–1136. 2016.(abstract in English). PubMed/NCBI
37	Wu J, Zhu D, Zhang J, Li G, Liu Z and Sun J: Lithium protects against methamphetamine-induced neurotoxicity in PC12 cells via Akt/GSK3β/mTOR pathway. Biochem Biophys Res Commun. 465:368–373. 2015. View Article : Google Scholar : PubMed/NCBI
38	Guo W, Qian L, Zhang J, Zhang W, Morrison A, Hayes P, Wilson S, Chen T and Zhao J: Sirt1 overexpression in neurons promotes neurite outgrowth and cell survival through inhibition of the mTOR signaling. J Neurosci Res. 89:1723–1736. 2011. View Article : Google Scholar : PubMed/NCBI
39	Zhou ZW, Li XX, He ZX, Pan ST, Yang Y, Zhang X, Chow K, Yang T, Qiu JX, Zhou Q, et al: Induction of apoptosis and autophagy via sirtuin1- and PI3K/Akt/mTOR-mediated pathways by plumbagin in human prostate cancer cells. Drug Des Devel Ther. 9:1511–1554. 2015. View Article : Google Scholar : PubMed/NCBI
40	Son Y, Cheong YK, Kim NH, Chung HT, Kang DG and Pae HO: Mitogen-activated protein kinases and reactive oxygen species: How can ROS activate MAPK pathways? J Signal Transduct 2011. 7926392011.
41	Gao L, Zhang L, Li N, Liu JY, Cai PL and Yang SL: New triterpenoid saponins from Patrinia scabiosaefolia. Carbohydr Res. 346:2881–2885. 2011. View Article : Google Scholar : PubMed/NCBI
42	Taguchi H and Endo T: Letter: Patrinoside, a new iridoid glycoside from Patrinia scabiosaefolia. Chem Pharm Bull. 22:1935–1937. 1974. View Article : Google Scholar : PubMed/NCBI
43	Nakanishi T, Tanaka K, Murata H, Somekawa M and Inada A: Phytochemical studies of seeds of medicinal plants. III. Ursolic acid and oleanolic acid glycosides from seeds of Patrinia scabiosaefolia Fischer. Chem Pharm Bull. 41:183–186. 1993. View Article : Google Scholar : PubMed/NCBI
44	Choi JS and Woo WS: Triterpenoid glycosides from the roots of Patrinia scabiosaefolia. Planta Med. 53:62–65. 1987. View Article : Google Scholar : PubMed/NCBI
45	Inada A, Yamada M, Murata H, Kobayashi M, Toya H, Kato Y and Nakanishi T: Phytochemical studies of seeds of medicinal plants. I. Two sulfated triterpenoid glycosides, sulfapatrinosides I and II, from seeds of Patrinia scabiosaefolia FISCHER. Chem Pharm Bull. 36:4269–4274. 1988. View Article : Google Scholar : PubMed/NCBI
46	Yang MY, Choi YH, Yeo H and Kim J: A new triterpene lactone from the roots of Patrinia scabiosaefolia. Arch Pharm Res. 24:416–417. 2001. View Article : Google Scholar : PubMed/NCBI