Open Access

Activation of the mTOR signaling pathway in breast cancer MCF‑7 cells by a peptide derived from Porphyra yezoensis

  • Authors:
    • Su-Jin Park
    • Jina Ryu
    • In-Hye Kim
    • Youn-Hee Choi
    • Taek-Jeong Nam
  • View Affiliations

  • Published online on: October 20, 2014     https://doi.org/10.3892/or.2014.3557
  • Pages: 19-24
  • Copyright: © Park et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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


Abstract

Seaweeds have beneficial nutritional and medicinal properties. Several studies have examined the polysaccharides found in the extracts of Porphyra yezoensis (PPY), although the effects of particular proteins have not been reported, and peptides from the marine alga PPY function in antitumor cell signaling, although the precise mechanism is not well understood. Apoptosis plays an important role in cell death, which affects cell proliferation. Generally, regulation of apoptosis requires participation of the p53 and Bcl-2 family by the mammalian target of rapamycin (mTOR) pathway, which is activated in a variety of malignant cancers. Autophagy is another signaling pathway that leads to degradation of cellular components by lysosomal activity, and the relationship between autophagy and cancer has been of interest for several years. The present study investigated mTOR pathway activation in MCF-7 cells treated with 500 ng PPY for 24 h by assessing LC3 as a monitor of autophagy. We observed that the p53/NF-κB and mTOR pathways were affected by PPY, which contributes to our understanding of the functional relationship between the Bcl-2 family and mTOR under apoptotic conditions in MCF-7 cells.

Introduction

Breast cancer is the most common malignancy and the second most common cause of cancer-related deaths in females in the Western world, with an estimated 192,370 new cases and 40,170 deaths in the US in 2009 (1). Although advances in chemotherapy have significantly reduced the risk of disease recurrence and death, the recurrence of breast cancer due to chemotherapy failure or acquired resistance remains a major challenge (2).

Mammalian target of rapamycin (mTOR) is a highly conserved 289-kDa Ser/Thr kinase found in yeast and all eukaryotes, consisting of two distinct signaling complexes known as mTORC1 and mTORC2. It belongs to the phosphoinositide 3-kinase (PI3K) family of protein kinases and regulates two important downstream substrates, p70S6 kinase (p70S6K) and eukaryotic initiation factor 4B binding protein 1 (4EBP1) (3). The mTOR pathway is a major regulator of autophagy activated downstream of PI3K-Akt, a pathway commonly dysregulated in human cancer (4) and activated by HER2, insulin-like growth factor receptor, and estrogen receptor in breast cancer (58), suggesting that it may play an important role in the development of cancer and many other diseases (9).

Apoptosis plays an important role in regulating cell death by controlling cell proliferation through p53 and Bcl-2 proteins. The Bcl-2 family is an important regulator of apoptosis (10,11) that includes anti-apoptotic and pro-apoptotic members, such as Bcl-2, Bcl-xL, Mcl-1 and Bax (12,13). The activation of Bcl-2 can be regulated by post-translational phosphorylation of Akt, mTOR, and p70S6K (14,15). Akt regulates cell survival via various molecular mechanisms that include phosphorylation and the inactivation of pro-apoptotic proteins, such as Bad, glycogen synthase kinase-3 (GSK-3), forkhead, and caspase-9 (16,17). As a downstream effector of PI3K/mTOR, Akt is constitutively activated in many types of human tumors, including breast cancer. Moreover, NF-κB and p53 signaling pathways are crucial modulators of cell survival and apoptosis (18,19), as well as important regulators of Bcl-2 family genes (2023).

Autophagy begins with the formation of double-membrane vesicles, known as autophagosomes, which engulf cytoplasmic constituents. The autophagosomes then fuse with lysosomes, allowing the sequestered contents to undergo degradation and recycling. Monoallelic loss of the essential autophagy gene, Beclin-1, has been found in 40–75% of human breast, prostate, and ovarian cancers, suggesting that autophagy may play a role in preventing these tumors (24). The production of inositol 1,4,5-triphosphate (PtIns3P) by Beclin-1 is essential for the recruitment of other autophagy-related gene (Atg) products critical for autophagosome formation. During the initiation phase, formation of the Atg5-Atg12 complex promotes the recruitment and conversion of cytosolic-associated protein light chain 3 (LC3-I) to LC3-II, the membrane-bound and lipidated form (25).

This study investigated mTOR pathway activation in MCF-7 cells treated with PPY by assessing LC3 to monitor autophagy. We observed that the p53/NF-κB and mTOR pathways were affected by PPY, which contributes to our understanding of the functional relationship between the Bcl-2 family and mTOR under apoptotic conditions in MCF-7 cells.

Materials and methods

Peptide preparation.

The PPY method was performed as previously described (26). Briefly, the peptide PPY, found in Porphyra yezoensis, was synthesized by PEPTRON (Daejeon, Korea). Purification of PPY was performed using a Shimadzu Prominence HPLC apparatus, controlled using the software package Class-VP, 6.14 (Kyoto, Japan), on a C18 column (Shiesido Capcell Pak) in 0.1% triflouroacetic (TFA)/water and a gradient of 10–70% acetonitrile in 0.1% TFA with a flow rate of 1 nm/min and UV detection at 220 nm.

Cell culture

Human breast cancer MCF-7 cells were obtained from the Korean Cell Line Bank (Seoul, Korea). Cells were maintained in RPMI-1640 supplemented with 10% fetal bovine serum, 100 μg/ml penicillin and 100 ng/ml streptomycin at 37°C in a humidified atmosphere with 5% CO2.

Western blot analysis

Proteins (50 μg/ml) were separated by 7.5–15% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to a polyvinylidene fluoride (PVDF) membrane (Millipore, Billerica, MA, USA). The membrane was blocked with 1% bovine serum albumin (BSA) in TBS-T (10 mM Tris-HCl, 150 mM NaCl, pH 7.5, 0.1% Tween-20) and then incubated overnight with the indicated primary antibodies (diluted 1:1,000) in TBS-T containing 1% BSA with gentle shaking at 4°C. The secondary antibody was a peroxidase-conjugated goat anti-mouse or rabbit antibody (diluted 1:10,000). Signals were detected using an enhanced chemiluminescence (ECL) western blotting kit (Amersham, Piscataway, NJ, USA).

siRNA transfection in vitro

The control and mTOR siRNA sequences were designed by cosmo GENETECH (Seoul, Korea). mTOR was targeted using the following siRNAs: sense, 5′-UGAACCCUGCCUUUGUCAUGC-3′ and antisense, 5′-GCAUGACAAAGGCAGGGUUCA-3′. Briefly, MCF-7 cells were transfected with the control, non-targeting or mTOR-targeted siRNAs using Lipofectamine (Invitrogen, Carlsbad, CA, USA) according to the manufacturer’s instructions. The cells were cultured in the presence of the transfection mixture for 72 h, and on the following day, the transfection mixture was replaced with fresh RPMI medium. After transfection, complete medium was added to a final volume of 1 ml, yielding a 50 nM final concentration of siRNA in each well. After a 24-h incubation at 37°C and 5% CO2, the transfected cells were refreshed with 1 ml complete media and returned to the incubator.

Results

Expression of the mTOR pathway in MCF-7 cells

PI3K/Akt signaling is crucial in a variety of divergent physiological processes, including transcription, differentiation, apoptosis, and metabolism (27). mTOR is a downstream kinase in the PI3K/Akt pathway whose activation is correlated with an increase in PI3K/Akt-dependent Ser2448 phosphorylation (28) and regulates cell growth by integrating nutrient- and growth factor-derived signals (29,30). Therefore, we examined activation of the mTOR pathway in MCF-7 cells (Fig. 1). There was a dose-dependent decrease in mTOR and p70S6K in the MCF-7 cells treated with PPY, which also decreased the level of phosphoinositide-dependent kinase 1 (PDK1). We previously demonstrated in MCF-7 cells that PPY increased the level of phosphatase and tensin homolog (PTEN) in a dose-dependent manner, which was accompanied by decreased ribosomal protein S6 (RPS6). These results demonstrate that PPY inhibits MCF-7 cell growth.

p70S6K plays an important role in metastasis

p70S6K has been associated with poor prognosis and metastasis in breast cancer, but the underlying mechanisms are not well understood. To determine the downstream targets and mechanisms that may play a role in metastasis, western blot analysis was used to detect proteins that may be critical in cell attachment, motility, invasion and metastasis (31). In a dose-dependent manner, PPY decreased activation of p70S6K in MCF-7 cells and downregulated transglutaminase 2 (TG2), β-catenin, and focal adhesion kinase phosphorylation (p-FAK) (Fig. 2). TG2 is a multifunctional enzyme known for its calcium-dependent post-translational covalent cross-linking of proteins (32,33), and TG2 expression on the cell membrane, as a result of its association with specific integrins, has been reported to promote cell survival signaling (34). These results demonstrated that p70S6K was involved in the metastasis of MCF-7 cells. In addition, p70S6K plays an important role in metastasis by regulating key proteins such as cyclin D1, PDCD4 and FAK, whereas E-cadherin, β-catenin and TG2 are essential for cell attachment, survival, and invasion, as well as metastasis in breast cancer (Fig. 3).

Activation of NF-κB and Bcl-2 family members

As shown in Fig. 4, the activities of NF-κB and Bcl-2 were decreased, while those of p53, Bad, and Bax were increased by PPY. This indicated that PPY controls apoptosis regulator gene expression by downregulation of p53 and upregulation of NF-κB to stimulate PPY-induced apoptosis in MCF-7 cells. Importantly, this study also showed that the p53/NF-κB and PI3K/Akt/mTOR pathways were affected by PPY, clarifying the functional relationship among NF-κB, Bcl-2 family genes and mTOR following PPY treatment. This demonstrated that PPY might modulate anticancer and Akt/mTOR signaling. NF-κB, which plays a pivotal role in cell survival, regulates a vast number of genes related to apoptosis, such as Bcl-2, Bax and Fas (35). Bcl-2 family members such as Bax and Bad promote apoptosis, whereas other members such as Bcl-2 and Bcl-xL exert anti-apoptotic effects (36).

The role of autophagy

Autophagy is important in a variety of other cellular processes, including the recycling of aged or damaged organelles, remodeling of cellular structures during development, cell death, and protection against bacterial infection (37). As shown in Fig. 5, we detected increased expression of autophagy-associated proteins such as LC3, Beclin-1, Atg5 and Atg7. When MCF-7 cells were treated with 500 ng/ml PPY for 24 h, an increase in LC3 protein expression was observed compared with the untreated cells. As a specific marker for autophagy, LC3 has been widely used to monitor autophagy. Lipidation of microtubule-associated protein LC3-1, an autophagy marker, coats autophagosomes during autophagy and is converted to LC3-II resulting in delayed electrophoretic mobility (38). Beclin-1 is an essential autophagic gene that contributes to initial vesicle nucleation and formation of the autophagosome, whereas Atg5 participates in autophagic vesicle elongation and completion (39). Fig. 6 summarizes what we know about the anatomy of autophagy and the role of Atg and other proteins involved in the formation and maturation of autophagosomes (40). These results support the idea that PPY induces autophagy, inhibits tumor growth and induces apoptosis in MCF-7 cells. In addition, we demonstrated that PPY-induced autophagy occurred via the Akt/mTOR pathway.

mTOR knockdown by PPY in MCF-7 cells

To further elucidate the role of PPY in autophagy, we used small interfering RNA (siRNA) conjugated with PPY to knock down mTOR expression in MCF-7 cells. MCF-7 cells were transfected with siRNA/Lipofectamine complexes using different PPY concentrations (0, 125, 250, 500 ng/ml). Total protein was harvested 3 days after siRNA treatment and western blot analysis was used to assess mTOR expression. There was a significant reduction in mTOR expression by siRNA when the PPY concentration was 500 ng/ml (Fig. 7). In addition, p70S6K and PDK protein levels were significantly suppressed by mTOR siRNA treatment in vitro compared with transfection of non-targeting siRNA controls.

Discussion

Cancer is caused by alterations in gene expression and is one of the major causes of mortality worldwide (29), since all cancers acquire resistance to long-term anticancer drug treatments. In the MCF-7 cells used in this study, we found that a peptide isolated from Porphyra yezoensis can target the mTOR signaling pathway, which has emerged as a critical regulator of cell proliferation, growth and translation (29). Recent studies have shown that aberrant activation of mTOR is involved in many cancers, including ovarian carcinoma, lung cancer, prostate cancer and mantle cell lymphoma (30). This study showed that PPY markedly decreased mTOR and p70S6K, and high concentrations of PPY decreased PDK1. Upon activation, mTOR and its downstream target p70S6K promoted cell growth by inducing protein synthesis (41). These results suggest that activation of mTOR plays an important role in the pathogenesis of MCF-7 cells.

The process of metastasis has three major steps. The first is the separation of cells from their original tissue; the second is immune surveillance in the circulation; and the third is the homing of cells to other tissues (31). In this study, we focused on metastasis since we wanted to determine the link between p70S6K and cell attachment proteins, such as TG2 and FAK, which were previously reported to be involved in metastasis (31). PPY decreased activation of p70S6K in MCF-7 cells and downregulated TG2, β-catenin and p-FAK proteins (Fig. 2). Downregulation of p70S6K also inhibited TG2 and β-catenin expression. These results demonstrated that p70S6K is involved in the metastasis of MCF-7 cells.

Expression of the apoptosis regulating factors, p53 and Bcl-2/Bax, correlates with apoptosis of cancer cells, including breast cancer (42). In the present study, we examined the involvement of p53 and Bcl-2 family members in PPY-induced apoptosis of MCF-7 cells. We found that the expression of NF-κB and Bcl-2 were decreased in the PPY-treated MCF-7 cells (Fig. 4). p53 modulates Bcl-2 during apoptosis in two ways: by direct trans-repression of Bcl-2 transcription and by transcription-independent, direct binding to Bcl-2 (40). p53 released from the p53-Bcl-2 complex can directly induce mitochondrial permeabilization and subsequent apoptosis (43). Importantly, these results are the first to show that PPY can regulate apoptosis regulator gene expression by downregulating NF-κB and upregulating p53 activity in MCF-7 cells. Additionally, PPY enhanced the mTOR/p70S6K signaling pathway in MCF-7 cells.

Autophagy is a catabolic process in which cells respond to various stress stimuli, such as hypoxia, nutrients, nutrient starvation and DNA damage (37). During this process, proteins or organelles, sequestered by double-membrane structures, fuse with lysosomes and are subsequently degraded by lysosomal hydrolases to be recycled and sustain metabolism (44). As shown in Fig. 5, we observed increased expression of autophagy-associated proteins LC3, Beclin-1, Atg5 and Atg7, revealing that PPY induced autophagy accompanied by apoptosis in MCF-7 cells. Collectively, these results indicate that autophagy provides a protective mechanism against PPY-induced apoptosis.

mTOR plays a critical role in cell cycle regulation, and rapamycin, a known inhibitor of mTOR (45), can inactivate mTOR specifically. Because mTOR regulates cell proliferation, it has been investigated extensively as a potent target for both anticancer and anti-restenotic therapies (46). Rapamycin and its analogues are reported to effectively prevent cardiac and pulmonary fibrosis in vivo (47,48), and mTOR promotes cell growth and proliferation by regulating protein synthesis. It is therefore conceivable that mTOR knockdown may also control or alter cell proliferation (49,50). Transfection of mTOR siRNA in MCF-7 cells downregulated mTOR expression, as monitored by western blotting. Knockdown of mTOR occurred only when the PPY concentration was 500 ng/ml. Compared with the non-targeting siRNA complexes, mTOR siRNA complexes reduced mTOR protein levels in MCF-7 cells (Fig. 7), confirming the suppression of targeted gene expression via RNA interference.

In conclusion, this study investigated the effect of PPY on the inhibition of MCF-7 cell proliferation, as well as the possible mechanism of growth inhibition. This study demonstrated the apoptosis of PPY cells and we identified regulation of the mTOR signaling pathway and autophagy in MCF-7 cells (Fig. 8).

Acknowledgements

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2012R1A6A1028677).

References

1 

American Cancer Society, Cancer Facts and Figures. American Cancer Society; Atlanta, GA: 2009

2 

He X, Wang Y, Zhu J, Orloff M and Eng C: Resveratrol enhances the anti-tumor activity of the mTOR inhibitor rapamycin in multiple breast cancer cell lines mainly by suppressing rapamycin-induced AKT signaling. Cancer Lett. 301:168–176. 2011. View Article : Google Scholar

3 

Hay N and Sonenberg N: Upstream and downstream of mTOR. Genes Dev. 18:1926–1945. 2004. View Article : Google Scholar : PubMed/NCBI

4 

Pattingre S, Espert L, Biard-Piechaczyk M and Codogno P: Regulation of macroautophagy by mTOR and Beclin1 complexes. Biochimie. 90:313–323. 2008. View Article : Google Scholar

5 

Bärlund M, Forozan F, Kononen J, et al: Detecting activation of ribosomal protein S6 kinase by complementary DNA and tissue microarray analysis. J Natl Cancer Inst. 92:1252–1259. 2000. View Article : Google Scholar : PubMed/NCBI

6 

Sekulic A, Hudson CC, Homme JL, et al: A direct linkage between the phosphosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 60:3504–3513. 2000.

7 

Lmoki K, Li Y, Zhu T, Wu J and Guan KL: TSC2 is phosphorylated and inhibited by AKT and suppresses mTOR signaling. Nat Cell Biol. 4:648–657. 2002. View Article : Google Scholar

8 

Chung J, Kuo CJ, Crabtree GR and Bieris J: Rapamycin FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell. 69:1227–1236. 1992. View Article : Google Scholar : PubMed/NCBI

9 

Holland EC, Sonenberg N, Pandolfi PP and Thomas G: Signaling control of mRNA translation in cancer pathogenesis. Oncogene. 23:3138–3144. 2004. View Article : Google Scholar : PubMed/NCBI

10 

Adams JM and Cory S: The Bcl-2 protein family: arbiters of cell survival. Science. 281:1322–1326. 1998. View Article : Google Scholar : PubMed/NCBI

11 

Antonsson B and Martinou JC: The Bcl-2 protein family. Exp Cell Res. 256:50–57. 2000. View Article : Google Scholar : PubMed/NCBI

12 

Yin XM, Oltvai ZN and Korsmeyer SJ: BH1 and BH2 domain of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature. 369:321–323. 1994. View Article : Google Scholar : PubMed/NCBI

13 

Reed JC: Bcl-2 family protein: regulators of apoptosis and chemo-resistance in hematologic malignancies. Semin Hematol. 34:9–19. 1997.PubMed/NCBI

14 

Johnstone RW, Ruefli AA and Lowe SW: Apoptosis: a link between cancer genetics and chemotherapy. Cell. 108:153–164. 2002. View Article : Google Scholar : PubMed/NCBI

15 

Malaguarnera L: Implications of apoptosis regulators in tumorigenesis. Cancer Metastasis Rev. 23:367–387. 2004. View Article : Google Scholar : PubMed/NCBI

16 

Khwaja A: Akt is more than just a Bad kinase. Nature. 401:33–34. 1999. View Article : Google Scholar : PubMed/NCBI

17 

McCormick F: Cancer: survival pathways meet their end. Nature. 428:267–269. 2004. View Article : Google Scholar : PubMed/NCBI

18 

Karin M, Cao Y, Greten FR and Li ZW: NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2:301–310. 2002. View Article : Google Scholar : PubMed/NCBI

19 

Steele RJ and Lane DP: p53 in cancer: a paradigm for modern management of cancer. Surgeon. 3:197–205. 2005. View Article : Google Scholar : PubMed/NCBI

20 

Haldar S, Negrini M, Monne M, Sabbioni S and Croce CM: Downregulation of Bcl-2 by p53 in breast cancer cells. Cancer Res. 54:2095–2097. 1994.PubMed/NCBI

21 

Miyashita T and Reed JC: Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 80:293–299. 1995. View Article : Google Scholar : PubMed/NCBI

22 

Bentires-Alj M, Dejardin E, Viatour P, Van Lint C, Froesch B, Reed JC, Mervile MP and Bours V: Inhibition of the NF-kappa B transcription factor increases Bax expression in cancer cell lines. Oncogene. 20:2805–2813. 2001. View Article : Google Scholar : PubMed/NCBI

23 

Heckman CA, Mehew JW and Boxer LM: NF-kappaB activates Bcl-2 expression in t(14;18) lymphoma cells. Oncogene. 21:3898–3908. 2002. View Article : Google Scholar : PubMed/NCBI

24 

Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh h and Troxel A: Promotion of tumorigenesis by heterozygous disruption of the beclin1 autophagy gene. J Clin Invest. 112:1809–1820. 2003. View Article : Google Scholar : PubMed/NCBI

25 

Matshushita M, Suzuki NN, Obara K, Fujioka Y, Ohsumi Y and Inagaki F: Structure of Atg5.Atg16, a complex essential for autophagy. J Biol Chem. 282:6763–6772. 2007. View Article : Google Scholar

26 

Park SJ, Ryu J, Kim IH, Choi YH and Nam TJ: Induction of apoptosis by a peptide from Porphyra yezoensis: regulation of the insulin-like growth factor I receptor signaling pathway in MCF-7 cells. Int J Oncol. 45:1011–1016. 2014.PubMed/NCBI

27 

Yuan TL and Cantley LC: PI3K pathway alterations in cancer: variations on theme. Oncogene. 27:5497–5510. 2008. View Article : Google Scholar : PubMed/NCBI

28 

Xu X, Sakon M, Nagano H, Hiraoka N, et al: Akt2 expression correlates with prognosis of human hepatocellular carcinoma. Oncol Rep. 11:25–32. 2004.

29 

Faivre S, Kroener G and Raymond E: Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 5:671–688. 2006. View Article : Google Scholar : PubMed/NCBI

30 

Dann SG and Thomas G: The amino acid sensitive TOR pathway from yeast to mammals. FEBS Lett. 580:2821–2829. 2006. View Article : Google Scholar : PubMed/NCBI

31 

Akar U, Ozpolat B, Mehta K, et al: Targeting p70S6k prevented lung metastasis in a breast cancer xenograft model. Mol Cancer Ther. 9:1180–1187. 2010. View Article : Google Scholar : PubMed/NCBI

32 

Fesus L and Szondy Z: Transglutaminase 2 in the balance of cell death and survival. FEBS Lett. 579:3297–3302. 2005. View Article : Google Scholar : PubMed/NCBI

33 

Herman JF, Mangala LS and Mehta K: Implications of increased tissue transglutaminase (TG2) expression in drug-resistant breast cancer (MCF-7) cells. Oncogene. 25:3049–3058. 2006. View Article : Google Scholar : PubMed/NCBI

34 

Fesus L and Piacentini M: Transglutaminase 2: an enigmatic enezyme with diverse function. Trends Biochem Sci. 27:534–539. 2002. View Article : Google Scholar : PubMed/NCBI

35 

Malek R, Borrowicz KK, Jargiełło M and Czuczwar SJ: Role of nuclear factor kappaB in the in the central nervous system. Pharmacological Rep. 59:25–33. 2007.

36 

Jurgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D and Reed JC: Bax directly induced release of cytochrome c from isolated mitochondria. Proc Natl Acad Sci USA. 95:4997–5002. 1998. View Article : Google Scholar

37 

Levine B and Kroemer G: Autophagy in the pathogenesis of disease. Cell. 132:27–42. 2008. View Article : Google Scholar : PubMed/NCBI

38 

Folkman J: Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 29:15–18. 2002. View Article : Google Scholar

39 

Zhang DM, Liu JS, Deng LJ, et al: Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway. Carcinogenesis. 34:1331–1342. 2013. View Article : Google Scholar : PubMed/NCBI

40 

Eskelinen FL: Maturation of autophagic vacuoles in Mammalian cells. Autophagy. 1:1–10. 2005. View Article : Google Scholar

41 

Jing Ji and Zheng PS: Activation of mTOR signaling pathway contributes to survival of cervical cancer cells. Gynecol Oncol. 117:103–108. 2010. View Article : Google Scholar

42 

Cho MY, Park SY, Park S, Lee YR, Han GD and Kim JA: Geranyl derivative of phloroacetophenone induces cancer cell-specific apoptosis through Bax-mediated mitochondrial pathway in MCF-7 human breast cancer cells. Biol Pharm Bull. 35:98–104. 2012. View Article : Google Scholar : PubMed/NCBI

43 

Lee KB, Byun HJ, Park SH, Park CY, Lee SH and Rho SB: CYR61 controls p53 and NF-κB expression through PI3K/AKT/mTOR pathways in carboplatin-induced ovarian cancer cells. Cancer Lett. 315:86–95. 2012. View Article : Google Scholar

44 

Klionsky DJ: The molecular machinery of autophagy: unanswered questions. J Cell Sci. 118:7–18. 2005. View Article : Google Scholar

45 

Dumont FJ and Su Q: Mechanism of action of the immunosuppressant rapamycin. Life Sci. 58:373–395. 1996. View Article : Google Scholar : PubMed/NCBI

46 

Windecker S, Roffi M and Meier B: Sirolimus eluting stent: a new era in interventional cardiology? Curr Pharm Des. 9:1077–1094. 2003. View Article : Google Scholar : PubMed/NCBI

47 

Gao XM, Wong G, Wang B, et al: Inhibition of mTOR reduces chronic pressure overload cardiac hypertrophy and fibrosis. J Hypertens. 24:1663–1670. 2006. View Article : Google Scholar : PubMed/NCBI

48 

Simler NR, Howell DC, Marshall RP, et al: The rapamycin analogue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rat. Eur Respir J. 19:1124–1127. 2002. View Article : Google Scholar : PubMed/NCBI

49 

Achenbach TV, Barrow RK and Heerneier K: Oligonucleotide-based knockdown technologies: antisense versus RNA interference. Chembiochem. 4:928–935. 2003. View Article : Google Scholar : PubMed/NCBI

50 

Burnet PE, Barrow RK, Cohen NA, Snyder SH and Sabatini DM: RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Nat Acad Sci USA. 95:1432–1437. 1998. View Article : Google Scholar

Related Articles

Journal Cover

January-2015
Volume 33 Issue 1

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
x
Spandidos Publications style
Park S, Ryu J, Kim I, Choi Y and Nam T: Activation of the mTOR signaling pathway in breast cancer MCF‑7 cells by a peptide derived from Porphyra yezoensis. Oncol Rep 33: 19-24, 2015
APA
Park, S., Ryu, J., Kim, I., Choi, Y., & Nam, T. (2015). Activation of the mTOR signaling pathway in breast cancer MCF‑7 cells by a peptide derived from Porphyra yezoensis. Oncology Reports, 33, 19-24. https://doi.org/10.3892/or.2014.3557
MLA
Park, S., Ryu, J., Kim, I., Choi, Y., Nam, T."Activation of the mTOR signaling pathway in breast cancer MCF‑7 cells by a peptide derived from Porphyra yezoensis". Oncology Reports 33.1 (2015): 19-24.
Chicago
Park, S., Ryu, J., Kim, I., Choi, Y., Nam, T."Activation of the mTOR signaling pathway in breast cancer MCF‑7 cells by a peptide derived from Porphyra yezoensis". Oncology Reports 33, no. 1 (2015): 19-24. https://doi.org/10.3892/or.2014.3557