Open Access

Grifola frondosa polysaccharides induce breast cancer cell apoptosis via the mitochondrial-dependent apoptotic pathway

  • Authors:
    • Yizhi Zhang
    • Dejun Sun
    • Qingjin Meng
    • Wanxu Guo
    • Qiuhui Chen
    • Ying Zhang
  • View Affiliations

  • Published online on: July 26, 2017     https://doi.org/10.3892/ijmm.2017.3081
  • Pages: 1089-1095
  • Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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


Abstract

Grifola frondosa, a type of food and medical fungus, has been shown to exhibit various pharmacological activities, including anticancer effects. As the most typical cancer diagnosed among female patients, breast cancer remains a huge concern threatening human health globally. In the present study, the anti-breast cancer effects of Grifola frondosa polysaccharides (GFPs) and the underlying mechanisms were investigated in MCF-7 and MDA-MB-231 cells, as well as in nude mice bearing MCF-7 tumor xenografts. GFPs exerted cytotoxic effects on the cells, as indicated by a decrease in cell viability, and an increase in the apoptototic rate, lactate dehydrogenase release and reactive oxygen species accumulation, inducing mitochondrial dysfunction. The increased expression of Bax, cleaved caspase-3 and caspase-8, and the reduced levels of B-cell lymphoma 2 (Bcl-2) and Bcl-extra large (Bcl‑xL) were observed in the cells incubated with GFPs and in the tumor tissues of the mice treated with GFPs. Moreover, the GFPs significantly suppressed the phosphorylation of AKT/glycogen synthase kinase-3β and extracellular signal-regulated kinases in a time-dependent manner. Finally, the inhibition of MCF-7 tumor xenograft growth further confirmed the anti-breast cancer effects of GFPs. All these findings revealed that GFPs induced human breast cancer cell apoptosis via the mitochondrial-dependent apoptotic pathway, and provide experimental evidence to support the use of Grifola frondosa as a potential treatment for breast cancer.

Introduction

According to the statistics, almost a quarter of female patients suffering from cancer are diagnosed with breast cancer (1). As the most typical type of cancer affecting women, even in an era with advanced medical applications, breast cancer remains a serious concernt and a threat to human health, causing significant morbidity and mortality (2). Several subtypes of breast cancer, each requiring different therapeutic regimens, limit the treatment options. The standard treatment for breast cancer is chemotherapy and radiotherapy; however, treatment outcomes are, in the most part, discouraging for patients (3). In this scenario, it is imperative to explore different alternative therapies or medicines with low toxicicity for breast cancer treatment.

Due to the significant cytotoxic activities and less adverse effects, herbal medicines have gradually become good candidates for cancer therapy (4). It has been proven that Cordyceps militaris, a folk tonic in Asia, displays pro-apoptotic properties in cells and tumor xenografts in C57BL/6 mice via mitochondrial-related pathways (5,6). As a type of food and medical fungus, Grifola frondosa has been studied for years, and amino acids, polysaccharides and amounts of trace elements have been found in its fruitbody. Since the first study on the anti-tumor effects of Grifola frondosa polysaccharide (GFP) in 1984, the structure and function of its polysaccharides have been gradually analyzed (7). Pharmacological analyses and clinical trials have demonstrated that the polysaccharide-enriched extract of Grifola frondosa exhibits various activities, including anti-tumor, immunomodulatory, and blood glucose and lipid regulating effects (810). A chemically sulfated polysaccharide purified from Grifola frondosa has also been shown to induce HepG2 cell apoptosis via the Notch 1-NF-κB pathway (11). However, few studies to date have reported the pro-apoptotic activities of GFP on breast cancer cells and the underlying mechanisms.

Apoptosis, an energy-dependent process, is regulated by various signals (12). During this process, cell shrinkage, chromatin condensation and DNA damage are observed (13). Mitochondrial apoptosis occurs gradually along with the depolarization of mitochondrial transmembrane potential (MMP; ΔΨm), the abnormal expressions of B-cell lymphoma 2 (Bcl-2) family members, cytochrome c (Cyto c) over-release and caspase-3 activation (14,15). The initiator caspase (caspase-8) controls the proteolytic maturation of caspase-3 (16). The accumulation of intracellular reactive oxygen species (ROS) is capable of inducing apoptosis by interacting with proteins related to mitochondrial dysfunction. On the other hand, the activation of AKT and extracellular signal-regulated kinases (ERKs) contributes to cell proliferation and apoptosis (17,18).

This study aimed to investigate the anti-breast cancer effects of GFP in in vitro and in vivo models. We found that in MCF-7 and MDA-MB-231 cells, GFP induced apoptotic cell death related to mitochondrial function. GFP also significantly suppressed the growth of MCF-7 tumor xenografts in nude mice. Our data support the possible use of Grifola frondosa as a therapeutic agent for breast cancer therapy.

Materials and methods

Preparation of polysaccharides separated from Grifola frondosa

Grifola frondosa powder (100 g) was extracted twice with 10-fold double-distilled water (DD water) at 90°C for 3 h. The protein existing in the extract was removed using Sevag reagent [v (n-butanol):v (chloroform) = 1:4, 50 ml]. Polysaccharides were collected via the alcohol precipitation method with 4-fold ethanol. The content of the total polysaccharides separated from Grifola frondosa was 65.2±1.05 mg/g.

Cell culture

The cell lines, MDA-MB-231 (human breast epithelial cell line; ATCC no. HTB-26) and MCF-7 (human breast carcinoma cell line; ATCC no. HTB-22), were maintained in Dulbecco's modified Eagle's medium (DMEM) medium, supplemented with a 10% fetal bovine serum (FBS), 100 U/ml penicillin and 100 g/ml streptomycin under a humidified atmosphere containing 5%/95% of CO2/air at 37°C. The cultured medium was refreshed every 3 days. Cell culture reagents were obtained from Invitrogen Life Technologies (Carlsbad, CA, USA).

MTT cell survival assay

The cells (5,000 cells/100 μl) were seeded into 96-well plates and incubated with GFPs at concentrations of 25, 50, 100, 200 and 400 μg/ml for 24 or 48 h. Subsequently, 10 μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (0.5 mg/ml) dissolved in phosphate-buffered saline (PBS) were added to each well. Following a 4-h incubation at 37°C in the dark, the supernatant was aspirated, and then 100 μl DMSO were added. The absorbance was measured at a wavelength of 540 nm using a microplate reader (Bio-Rad Laboratories, Inc., Hercules, CA, USA). Values were expressed as a percentage of those from the corresponding controls.

Analysis of lactate dehydrogenase (LDH) concentration and caspase-3 activation

The cells (5×104) were seeded into 6-well plates and treated with 50 and 200 μg/ml GFPs for 24 h. The LDH concentration in the culture medium was detected using a LDH assay kit (Nanjing Jiancheng Bioengineering Institute, Nanjing, China) according to the manufacturer's instructions.

The treated cells were collected and lysed with radioimmunoprecipitation assay (RIPA) buffer (Sigma-Aldrich, St. Louis, MO, USA), and the protein concentration was examined using Bio-Rad protein assays. A caspase-3 colorimetric detection kit (Enzo Life Sciences, Inc., Farmingdale, NY, USA) was applied to detect caspase-3 activation. Values were expressed as a percentage of those from the corresponding controls.

Flow cytometric analysis of cell apoptosis

The cells were seeded into 6-well plates at 5×104/well and treated with 50 and 200 μg/ml GFPs for 12 h. The treated cells were harvested and washed with PBS 3 times, and then suspended in binding buffer containing with 5 μl Annexin V-FITC (20 μg/ml) and 5 μl propidium iodide (PI; 50 μg/ml) (BD Biosciences, Franklin Lakes, NJ, USA). Following a 15-min incubation at room temperature in the dark, the apoptotic rate was analyzed using a flow cytometer (FC500; Beckman Coulter, Inc., Brea, CA, USA).

Detection of ROS

Following treatment with GFPs for 12 h at concentrations of 50 and 200 μg/ml, the cells were suspended and incubated with 10 μM dichlorodihydrofluorescein diacetate (DCFH-DA) for 10 min at 37°C in the dark. After being washed with PBS 3 times, the intracellular ROS levels were determined using a flow cytometer (FC500; Beckman Coulter).

Detection of MMP

The cells were seeded into 6-well plates at 5×104/well and treated with 50 and 200 μg/ml GFPs for 12 h. The cells were further incubated with 2 μM 5,5′,6,6′-tetra-chloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide (JC-1; Sigma-Aldrich) at 37°C for 10 min. After being washed with PBS, the changes in fluorescent color were examined using a fluorescence microscope (x20 magnification; CCD camera, TE2000; Nikon, Tokyo, Japan).

MCF-7 tumor xenograft model

Six-week-old male BALB/c nude mice purchased from Weitong Lihua Laboratory Animal Technology Ltd. Co. (Beijing, China) were used in our in vivo experiments. The protocol was approved by the Animal Ethics Committee of Jilin University. The mice were housed in groups 3 per cage and maintained on a 12 h light/dark cycle at 23±1°C with water and food available ad libitum.

An amount of 0.1 ml (1×108 cells/ml) of MCF-7 cells at the mid-log phase was inoculated subcutaneously into the right flank of BALB/c nude mice. When the diameter of the tumor reached to 3–5 mm, the mice were divided into 2 groups (n=3 each) randomly, and orally treated with 0.5 g/kg GFPs or DD water every other day continuously for 2 weeks. During the GFP administration, the body weight and tumor dimension were measured. The equation of length × (width)2 × 0.5 was applied to estimate the tumor volume (mm3). All the mice were sacrificed via an injection of 200 mg/kg pentobarbital after the final treatment, and tumor tissues were dissected.

Western blot analysis

The MCF-7 or MDA-MB-231 (2×105 cells) were seeded into 6-well plates and exposed vaqrious concentrations of GFPs for the indicated periods of time. The cells and collected tumor tissues were lysed by RIPA buffer containing 1% protease inhibitor cocktail and 2% phenylmethanesulfonyl fluoride (PMSF) (both from Sigma-Aldrich). The bicinchoninic acid method was applied to detect the protein concentrations. Protein samples (40 μg) were separated on a 12% SDS-PAGE gel, and then electroblotted onto nitrocellulose membranes (0.45 μm; Bio Basic, Inc., Markham, ON, Canada). The membranes were incubated at 4°C overnight with Bcl-2 (MABC573), Bcl-extra large (Bcl-xL; MAB4625), Bax (AB2915), cleaved caspase-3 (AB3623), cleaved caspase-8 (AB1879), and phosphorylated (p)-AKT (05–1003) (all from Merck Millipore, Darmstadt, Germany), total (t)-AKT (ab126811) and p-glycogen synthase kinase-3β (GSK-3β) (ab75745) (both from Abcam, Cambrige, UK), T-GSK-3β (PK1111) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (ABS16) (both from Merck Millipore) at dilution of 1:1,000. The membranes were then incubated with horseradish peroxidase-conjugated secondary antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA) for 2 h at room temperature. Band detection was performed using enhanced chemiluminescence (ECL) detection kits (GE Healthcare Life Sciences, Chalfont, UK). The intensity of the bands was quantified using ImageJ software.

Statistical analysis

Data are expressed as the means ± standard deviation (SD) and analyzed by a one-way analysis of variance (ANOVA) followed with Dunn's test using SPSS software (SPSS, Inc., Chicago, IL, USA). The IC50 values are calculated using SPSS 16.0 software (IBM Corporation, Armonk, NY, USA). A value P<0.05 was considered to indicate a statistically significant difference.

Results

Intracellular toxic effects of GFPs on breast cancer cells

The 24-h IC50 values of the GFPs were 335 and 412 μg/ml, and the 48-h IC50 values of the GFPs were 295 and 348 µg/ml in the MCF-7 and MDA-MB-231 cells, respectively (Fig. 1A and B). The release of LDH was increased during cell death. An approximately 47 and 32% LDH over-release was observed in the 200 µg/ml GFP-treated MCF-7 and MDA-MB-231 cells (P<0.01; Fig. 1C). The activation of caspase-3 serves as a marker of cell apoptosis. We found that the GFPs at 200 µg/ml enhanced caspase-3 activation by almost 35 and 43% in the MCF-7 and MDA-MB-231 cells, respectively (P<0.01; Fig. 1D).

In addition, incubation with the GFPs (50 μg/ml) for 12 h led to approximately 22 and 21% of the MCF-7 and MDA-MB-231 cells, respectively to become apoptotic (Fig. 2A). Furthermore, oxidative stress, particularly, the overproduction of intracellular ROS, leads to cellular dysfunction and apoptosis (19). In this study, following incubation with the GFPs for 12 h at 200 μg/ml, a 50 and 26% increment in intracellular ROS levels was noted in the MCF-7 and MDA-MB-231 cells, respectively compared with the controls (Fig. 2B). All these data confirmed that GFPs exerted cytotoxic effects on the MCF-7 and MDA-MB-231 cells.

GFPs cause mitochondrial dysfunction

Mitochondrial function plays a central role during cell apoptosis (20). As indicated by the reduced ratio of red to green fluorescence by JC-1 staining, treatment with the GFPs for 12 h at concentrations of 50 and 200 μg/ml significantly decreased MMP in the MCF-7 and MDA-MB-231 cells, compared with untreated cells (Fig. 3A). Furthermore, the increased expression levels of Bax, cleaved caspase-3 and caspase-8, and the reduced levels of Bcl-2 and Bcl-xL were observed in the MCF-7 and MDA-MB-231 cells following incubation with the GFPs for 24 h GFPs at concentrations of 50 and 200 μg/ml (Fig. 3B).

The activation of AKT/GSK-3β and ERK is involved in GFP-mediated cytotoxicity in breast cancer cells

It has been reported that the activation of AKT/GSK-3β and ERK participate in cell proliferation, survival and even apoptosis (21,22). The GFPs time-dependently suppressed the phosphorylation of AKT and GSK-3β from 0.5 to 3 h in the breast cancer cells incubated with 200 μg/ml of GFPs, particularly at 1 and 3 h (Fig. 4). In addition, incubation with 200 μg/ml GFPs significantly inhibited the activation of ERK from 1 and 3 h in the MCF-7 and MDA-MB-231 cells (Fig. 4).

GFPs inhibits the growth of MCF-7 tumor xenografts

GFP administration at 0.5 g/kg significantly suppressed the growth of MCF-7 tumor xenografts from the 8th day to the end of the experiment (P<0.05; Fig. 5A and C). Compared with the controls, GFPs decreased the tumor size by almost 42% on the 14th day (P<0.01; Fig. 5C). The GFPs did not to influence the body weight of the mice compared with the untreated mice, which suggested limited aggressive side-effects (Fig. 5B). Additionally, compared with the controls, in the tumor tissues from the treated mice, GFPs increased the expression levels of Bax, cleaved caspase-3 and caspase-8, and suppressed the expression levels of Bcl-2 and Bcl-xL (Fig. 5D).

Discussion

In the present study, the potential anti-tumor effects of GPFs on breast cancer were successfully confirmed in MCF-7 and MDA-MB-231 cells, and tumor-bearing nude mice. The GFPs exerted cytotoxic effects on the breast cancer cell lines, as evidenced by a decrease in cell viability, and an increase in LDH release, ROS accumulation and caspase-3 activation, as well as the induction of cell apoptosis and mitochondrial apoptotic alterations. The suppressed phosphorylation of AKT/GSk-3β and ERK, related to mitochondrial function, revealed the possible mechanisms involved.

During apoptosis, which is a physiological suicide process, mitochondrial function plays a central role (23). The functional loss of the mitochondria is related to the dissipation of MMP (20), which was noted in this study following incubation with the GFPs for 12 h. The reduced Bcl-2 and Bcl-xL levels, and enhanced Bax expression levels were also observed in the GFP-treated cells. The Bcl-2 family, located in the outer mitochondrial membrane, serves as an important index in mitochondrial-mediated apoptosis (24). Moreover, in this study, the accumulation of intracellular ROS was observed in the cells treated with the GFPs. The overproduction of ROS causes oxidative stress, further resulting in mitochondrial apoptosis and cellular dysfunction. It has been reported that ROS accumulation is responsible for the opening mitochondrial permeability transition pore (mPTP), which leads to mitochondrial depolarization, matrix solutes loss and Cyto c release (25). Taken together, the effects of GFPs on mitochondrial function are involved in its anti-breast cancer effects.

On the other hand, mitochondria control the intrinsic pathway of apoptosis, and during this process, MMP ignites caspases and other catabolic enzyme activation (26). Caspases are considered as inactive pro-enzymes and will be activated via proteolytic cleavage (27). Caspase-8, located mostly in the mitochondria, undergoes dimerization, and then cleaves itself to its fully activated form (28), which further leads to the cleavages of effector caspases in the cytosol (caspase-3) (29). Caspase-3, amplifying the initiation signals from caspase-8, plays a central role in activating the apoptotic program via regulating other caspases and some vital proteins (30), and it is important for cell death in a tissue-, cell type- or death stimulus-specific manner (31). In this study, in MCF-7 and MDA-MB-231 cells, and MCF-7 tumor xenografts, GFPs significantly enhanced the expressions of cleaved caspase-3 and caspase-8, which revealed that the anticancer activity of GFPs was associated with the regulation on caspase activation, which further targets the mitochondria.

AKT signaling is responsible for cell proliferation and apoptosis, which regulates apoptotic proteins including Bcl-2 family members GSK-3β (21). The reduced phosphorylation of AKT activates its downstream GSK-3β, which promotes Bax activation (32). As previously reported, GSK-3β mediates the release of cytochrome c into the cytosol, and its activated form helps to open mPTP (33). Via the AKT/GSK-3β- and ROS-dependent mitochondrial-mediated pathway, 18β-glycyrrhetinic acid induces the apoptosis of pituitary adenoma cells (23). Furthermore, the ERK pathway has been reported to be a target for cancer therapy, which is hyper-acted in human tumors (34,35). p-ERK, an active form, inhibits pro-apoptotic signals via the modulation of numerous substrates (22). In our study, the GFPs strongly suppressed the phosphorylation of AKT/GSK-3β and ERK in the MCF-7 and MDA-MB-231 cells, and this suppression may be involved in the GFP-mediated anti-tumor effects. Furthermore, ERK has been shown to exert positive regulatory effects on Bcl-2 and Bcl-xL expression, and ERKs/Bcl-2 have been confirmed as potential targets for cancer cell apoptosis (36,37). Previous studies have indicated that AKT contributes to the maintenance of mitochondrial integrity, which also affects Bcl-2 expression (38,39). Collectively, the downregulation of AKT/GSK-3β and ERK activation contributes to GFP-induced mitochondrial apoptosis.

The anti-breast cancer effects of GFPs were successfully confirmed in in vitro and in vivo experiments. GFPs reduced cell viability, enhanced the apoptotic rate, increased the ROS and caspase-3 intracellular levels, and caused LDH over-release, as well as MMP dissipation and the abnormal expression of pro-apoptotic proteins. The suppressed activation of ERK and AKT/GSK-3β in the GFP-incubated cells was responsible for mitochondrial dysfunction. All these findings reveal that the mitochondrial-dependent apoptotic pathway contributes to GFP-induced cytotoxicity in the MCF-7 and MDA-MB-231 cells, which provides pharmacological evidence to support the use of GFPs as a potential chemotherapeutic agent.

Acknowledgments

This study was supported by Jilin Province Science and Technology Key Problem of China (2014020314YY).

References

1 

Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI

2 

Hosseini BA, Pasdaran A, Kazemi T, Shanehbandi D, Karami H, Orangi M and Baradaran B: Dichloromethane fractions of Scrophularia oxysepala extract induce apoptosis in MCF-7 human breast cancer cells. Bosn J Basic Med Sci. 15:26–32. 2015. View Article : Google Scholar : PubMed/NCBI

3 

Chang CH, Chen SJ and Liu CY: Adjuvant treatments of breast cancer increase the risk of depressive disorders: a population-based study. J Affect Disord. 182:44–49. 2015. View Article : Google Scholar : PubMed/NCBI

4 

Vadodkar AS, Suman S, Lakshmanaswamy R and Damodaran C: Chemoprevention of breast cancer by dietary compounds. Anticancer Agents Med Chem. 12:1185–1202. 2012. View Article : Google Scholar : PubMed/NCBI

5 

Jin CY, Kim GY and Choi YH: Induction of apoptosis by aqueous extract of Cordyceps militaris through activation of caspases and inactivation of Akt in human breast cancer MDA-MB-231 cells. J Microbiol Biotechnol. 18:1997–2003. 2008.

6 

Yoo HS, Shin JW, Cho JH, Son CG, Lee YW, Park SY and Cho CK: Effects of Cordyceps militaris extract on angiogenesis and tumor growth. Acta Pharmacol Sin. 25:657–665. 2004.PubMed/NCBI

7 

Ohno N, Suzuki I, Oikawa S, Sato K, Miyazaki T and Yadomae T: Antitumor activity and structural characterization of glucans extracted from cultured fruit bodies of Grifola frondosa. Chem Pharm Bull (Tokyo). 32:1142–1151. 1984. View Article : Google Scholar

8 

Inoue A, Kodama N and Nanba H: Effect of maitake (Grifola frondosa) D-fraction on the control of the T lymph node Th-1/Th-2 proportion. Biol Pharm Bull. 25:536–540. 2002. View Article : Google Scholar : PubMed/NCBI

9 

Ma XL, Meng M, Han LR, Li Z, Cao XH and Wang CL: Immunomodulatory activity of macromolecular polysaccharide isolated from Grifola frondosa. Chinese Journal of Natural Medicines. 13:906–914. 2015. View Article : Google Scholar

10 

Cui FJ, Li Y, Xu YY, Liu ZQ, Huang DM, Zhang ZC and Tao WY: Induction of apoptosis in SGC-7901 cells by polysaccharide-peptide GFPS1b from the cultured mycelia of Grifola frondosa GF9801. Toxicol In Vitro. 21:417–427. 2007. View Article : Google Scholar

11 

Wang CL, Meng M, Liu SB, Wang LR, Hou LH and Cao XH: A chemically sulfated polysaccharide from Grifola frondos induces HepG2 cell apoptosis by notch1-NF-κB pathway. Carbohydr Polym. 95:282–287. 2013. View Article : Google Scholar : PubMed/NCBI

12 

Nakagawa S, Shiraishi T, Kihara S and Tabuchi K: Detection of DNA strand breaks associated with apoptosis in human brain tumors. Virchows Arch. 427:175–179. 1995. View Article : Google Scholar : PubMed/NCBI

13 

Joselin AP, Schulze-Osthoff K and Schwerk C: Loss of Acinus inhibits oligonucleosomal DNA fragmentation but not chromatin condensation during apoptosis. J Biol Chem. 281:12475–12484. 2006. View Article : Google Scholar : PubMed/NCBI

14 

Chen R, Liu S, Piao F, Wang Z, Qi Y, Li S, Zhang D and Shen J: 2,5-Hexanedione induced apoptosis in mesenchymal stem cells from rat bone marrow via mitochondria-dependent caspase-3 pathway. Ind Health. 53:222–235. 2015. View Article : Google Scholar : PubMed/NCBI

15 

Wang Y, Wu Y, Luo K, Liu Y, Zhou M, Yan S, Shi H and Cai Y: The protective effects of selenium on cadmium-induced oxidative stress and apoptosis via mitochondria pathway in mice kidney. Food Chem Toxicol. 58:61–67. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Hu Q, Wu D, Chen W, Yan Z and Shi Y: Proteolytic processing of the caspase-9 zymogen is required for apoptosome-mediated activation of caspase-9. J Biol Chem. 288:15142–15147. 2013. View Article : Google Scholar : PubMed/NCBI

17 

Lin YL, Wang GJ, Huang CL, Lee YC, Liao WC, Lai WL, Lin YJ and Huang NK: Ligusticum chuanxiong as a potential neuroprotectant for preventing serum deprivation-induced apoptosis in rat pheochromocytoma cells: functional roles of mitogen-activated protein kinases. J Ethnopharmacol. 122:417–423. 2009. View Article : Google Scholar : PubMed/NCBI

18 

Lou H, Fan P, Perez RG and Lou H: Neuroprotective effects of linarin through activation of the PI3K/Akt pathway in amyloid-β-induced neuronal cell death. Bioorg Med Chem. 19:4021–4027. 2011. View Article : Google Scholar : PubMed/NCBI

19 

Brown DI and Griendling KK: Regulation of signal transduction by reactive oxygen species in the cardiovascular system. Circ Res. 116:531–549. 2015. View Article : Google Scholar : PubMed/NCBI

20 

Hisatomi T, Ishibashi T, Miller JW and Kroemer G: Pharmacological inhibition of mitochondrial membrane permeabilization for neuroprotection. Exp Neurol. 218:347–352. 2009. View Article : Google Scholar : PubMed/NCBI

21 

Maurer U, Preiss F, Brauns-Schubert P, Schlicher L and Charvet C: GSK-3 - at the crossroads of cell death and survival. J Cell Sci. 127:1369–1378. 2014. View Article : Google Scholar : PubMed/NCBI

22 

Sweatt JD: The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem. 76:1–10. 2001. View Article : Google Scholar : PubMed/NCBI

23 

Wang D, Wong HK, Feng YB and Zhang ZJ: 18beta-glycyrrhetinic acid induces apoptosis in pituitary adenoma cells via ROS/MAPKs-mediated pathway. J Neurooncol. 116:221–230. 2014. View Article : Google Scholar

24 

Chan SL and Yu VC: Proteins of the bcl-2 family in apoptosis signalling: from mechanistic insights to therapeutic opportunities. Clin Exp Pharmacol Physiol. 31:119–128. 2004. View Article : Google Scholar : PubMed/NCBI

25 

Bernardi P and Rasola A: Calcium and cell death: the mitochondrial connection. Subcell Biochem. 45:481–506. 2007. View Article : Google Scholar

26 

Galluzzi L, Vitale I, Kepp O, Séror C, Hangen E, Perfettini JL, Modjtahedi N and Kroemer G: Methods to dissect mitochondrial membrane permeabilization in the course of apoptosis. Methods Enzymol. 442:355–374. 2008. View Article : Google Scholar : PubMed/NCBI

27 

Hippe D, Gais A, Gross U and Lüder CG: Modulation of caspase activation by Toxoplasma gondii. Methods Mol Biol. 470:275–288. 2009. View Article : Google Scholar

28 

Schug ZT, Gonzalvez F, Houtkooper RH, Vaz FM and Gottlieb E: BID is cleaved by caspase-8 within a native complex on the mitochondrial membrane. Cell Death Differ. 18:538–548. 2011. View Article : Google Scholar :

29 

Lee KH, Feig C, Tchikov V, Schickel R, Hallas C, Schütze S, Peter ME and Chan AC: The role of receptor internalization in CD95 signaling. EMBO J. 25:1009–1023. 2006. View Article : Google Scholar : PubMed/NCBI

30 

Espín R, Roca FJ, Candel S, Sepulcre MP, González-Rosa JM, Alcaraz-Pérez F, Meseguer J, Cayuela ML, Mercader N and Mulero V: TNF receptors regulate vascular homeostasis in zebrafish through a caspase-8, caspase-2 and P53 apoptotic program that bypasses caspase-3. Dis Model Mech. 6:383–396. 2013. View Article : Google Scholar :

31 

Porter AG and Jänicke RU: Emerging roles of caspase-3 in apoptosis. Cell Death Differ. 6:99–104. 1999. View Article : Google Scholar : PubMed/NCBI

32 

Zhang L, Zhang Y and Xing D: LPLI inhibits apoptosis upstream of Bax translocation via a GSK-3beta-inactivation mechanism. J Cell Physiol. 224:218–228. 2010.PubMed/NCBI

33 

Petit-Paitel A, Brau F, Cazareth J and Chabry J: Involvment of cytosolic and mitochondrial GSK-3beta in mitochondrial dysfunction and neuronal cell death of MPTP/MPP-treated neurons. PLoS One. 4:e54912009. View Article : Google Scholar : PubMed/NCBI

34 

Krajarng A, Nakamura Y, Suksamrarn S and Watanapokasin R: α-Mangostin induces apoptosis in human chondrosarcoma cells through downregulation of ERK/JNK and Akt signaling pathway. J Agric Food Chem. 59:5746–5754. 2011. View Article : Google Scholar : PubMed/NCBI

35 

Tada K, Kawahara K, Matsushita S, Hashiguchi T, Maruyama I and Kanekura T: MK615, a Prunus mume Steb. Et Zucc ('Ume') extract, attenuates the growth of A375 melanoma cells by inhibiting the ERK1/2-Id-1 pathway. Phytother Res. 26:833–838. 2012. View Article : Google Scholar

36 

Zhao Y, Shen S, Guo J, Chen H, Greenblatt DY, Kleeff J, Liao Q, Chen G, Friess H and Leung PS: Mitogen-activated protein kinases and chemoresistance in pancreatic cancer cells. J Surg Res. 136:325–335. 2006. View Article : Google Scholar : PubMed/NCBI

37 

Balmanno K and Cook SJ: Tumour cell survival signalling by the ERK1/2 pathway. Cell Death Differ. 16:368–377. 2009. View Article : Google Scholar

38 

Lim JY, Park SI, Oh JH, Kim SM, Jeong CH, Jun JA, Lee KS, Oh W, Lee JK and Jeun SS: Brain-derived neurotrophic factor stimulates the neural differentiation of human umbilical cord blood-derived mesenchymal stem cells and survival of differentiated cells through MAPK/ERK and PI3K/Akt-dependent signaling pathways. J Neurosci Res. 86:2168–2178. 2008. View Article : Google Scholar : PubMed/NCBI

39 

Ma R, Xiong N, Huang C, Tang Q, Hu B, Xiang J and Li G: Erythropoietin protects PC12 cells from beta-amyloid(25–35)-induced apoptosis via PI3K/Akt signaling pathway. Neuropharmacology. 56:1027–1034. 2009. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

October 2017
Volume 40 Issue 4

Print ISSN: 1107-3756
Online ISSN:1791-244X

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Zhang, Y., Sun, D., Meng, Q., Guo, W., Chen, Q., & Zhang, Y. (2017). Grifola frondosa polysaccharides induce breast cancer cell apoptosis via the mitochondrial-dependent apoptotic pathway. International Journal of Molecular Medicine, 40, 1089-1095. https://doi.org/10.3892/ijmm.2017.3081
MLA
Zhang, Y., Sun, D., Meng, Q., Guo, W., Chen, Q., Zhang, Y."Grifola frondosa polysaccharides induce breast cancer cell apoptosis via the mitochondrial-dependent apoptotic pathway". International Journal of Molecular Medicine 40.4 (2017): 1089-1095.
Chicago
Zhang, Y., Sun, D., Meng, Q., Guo, W., Chen, Q., Zhang, Y."Grifola frondosa polysaccharides induce breast cancer cell apoptosis via the mitochondrial-dependent apoptotic pathway". International Journal of Molecular Medicine 40, no. 4 (2017): 1089-1095. https://doi.org/10.3892/ijmm.2017.3081