Inscrição na biblioteca: Guest
Portal Digital Begell Biblioteca digital da Begell eBooks Diários Referências e Anais Coleções de pesquisa
International Journal of Medicinal Mushrooms
Fator do impacto: 1.423 FI de cinco anos: 1.525 SJR: 0.431 SNIP: 0.716 CiteScore™: 2.6

ISSN Imprimir: 1521-9437
ISSN On-line: 1940-4344

Volume 22, 2020 Volume 21, 2019 Volume 20, 2018 Volume 19, 2017 Volume 18, 2016 Volume 17, 2015 Volume 16, 2014 Volume 15, 2013 Volume 14, 2012 Volume 13, 2011 Volume 12, 2010 Volume 11, 2009 Volume 10, 2008 Volume 9, 2007 Volume 8, 2006 Volume 7, 2005 Volume 6, 2004 Volume 5, 2003 Volume 4, 2002 Volume 3, 2001 Volume 2, 2000 Volume 1, 1999

International Journal of Medicinal Mushrooms

DOI: 10.1615/IntJMedMushrooms.2019032888
pages 1151-1165

Activation of the AKT/FOXO3a Signaling Pathway during Breast Cancer Inhibition In Vivo and In Vitro by Amauroderma rude (Agaricomycetes)

Honghui Pan
Guangdong Institute of Microbiology, State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangzhou, P.R. China
Suwei Lei
Guangdong Institute of Microbiology, State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangzhou, P.R. China
Xiaojie Zhao
Guangdong Institute of Microbiology, State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangzhou, China
Yi-Zhen Xie
Guangdong Institute of Microbiology, State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangzhou, P.R. China; Yuewei Edible Fungi Technology Co. Ltd., Guangzhou, P.R. China
Xiaobing Yang
Guangdong Institute of Microbiology, State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Open Laboratory of Applied Microbiology, Guangzhou, China


We previously reported that Amauroderma rude polysaccharides (AR) displayed strong immunomodulatory tumor-suppressive effects in mice. The current study was designed to explore the potential mechanism by which AR polysaccharides inhibit tumor growth. We found that AR could effectively induce cell death in 4T1 and MDA-MB-231 breast cancer cells. AR could also inhibit tumor cell migration and invasion, significantly promote apoptosis in 4T1 cells, and significantly increase CDK4, CDK6, cylinD1, and P27 mRNA expression in mice. Additionally, AR was able to significantly increase FOXO3a expression and decrease p-AKT expression both in vitro and in vivo, indicating that the AKT/FOXO3a signaling pathway had been activated during the inhibitory process.


  1. Sun X, Liu N, Wu Z, Feng Y, Meng X. Anti-tumor activity of a polysaccharide from blueberry. Molecules. 2015;20:3841-53.

  2. Wu J, Wu Y, Yang BB. Anticancer activity of Hemsleya amabilis extract. Life Sci. 2002;71:2161-70.

  3. Horng CT, Huang JK, Wang HY, Huang CC, Chen FA. Antioxidant and antifatigue activities of Polygonatum Alte-lobatum Hayata rhizomes in rats. Nutrients. 2014;6:5327-37.

  4. Hsu HY, Lin TY, Wu YC, Tsao SM, Hwang PA, Shih YW, Hsu J. Fucoidan inhibition of lung cancer in vivo and in vitro: role of the Smurf2-dependent ubiquitin proteasome pathway in TGFbeta receptor degradation. Oncotarget. 2014;5:7870-85.

  5. Lu WJ, Chang NC, Jayakumar T, Liao JC, Lin MJ, Wang SH, Chou DS, Thomas PA, Sheu JR. Ex vivo and in vivo studies of CME-1, a novel polysaccharide purified from the mycelia of Cordyceps sinensis that inhibits human platelet activation by activating adenylate cyclase/cyclic AMP. Thromb Res. 2014;134:1301-10.

  6. Pan HH, Yu XT, Li T, Wu HL, Jiao CW, Cai MH, Li XM, Xie YZ, Wang Y, Peng T. Aqueous extract from a Chaga medicinal mushroom, Inonotus obliquus (higher Basidiomycetes), prevents herpes simplex virus entry through inhibition of viral-induced membrane fusion. Int J Med Mushrooms. 2013;15:29-38.

  7. Wei D, Chen T, Yan M, Zhao W, Li F, Cheng W, Yuan L. Synthesis, characterization, antioxidant activity and neuroprotective effects of selenium polysaccharide from Radix hedysari. Carbohydr Polym. 2015;125:161-8.

  8. Hibbett DS, Binder M, Bischoff JF, Blackwell M, Cannon PF, Eriksson OE, Huhndorf S, James T, Kirk PM. A higher-level phylogenetic classification of the Fungi. Mycol Res. 2007;111(5):509-47.

  9. Jia DH, Zheng LY, Zhang XP, Peng WH. Study and analysis of the taxonomy situation for genus ganoderma. Southwest China J Agr Sci. 2003;S1(16):64-8.

  10. Chan PM, Kanagasabapathy G, Tan YS, Sabaratnam V, Kuppusamy UR. Amauroderma rugosum (Blume & T. Nees) Torrend: nutritional composition and antioxidant and potential anti-inflammatory properties. Evid Based Complement Alternat Med. 2013;304713.

  11. Zhang SS, Ma QY, Zou XS, Dai HF, Huang SZ, Luo Y, Yu ZF, Luo HR, Zhao YX. Chemical constituents from the fungus Amauroderma amoiensis and their in vitro acetylcholinesterase inhibitory activities. Planta Med. 2013;79:87-91.

  12. Pan HH, Zhang YF, Liang BS, Zhao XJ, Yang XB, Xie YZ. Acute and subchronic toxicity of dusky-skinned mushroom, Amauroderma rude (Agaricomycetes). Int J Med Mushrooms. 2017;19(8):727-35.

  13. Pan HH, Han YY, Huang JG, Yu XT, Jiao CW, Yang XB, Dhaliwal P, Xie YZ, Yang BB. Purification and identification of a polysaccharide from medicinal mushroom Amauroderma rude with immunomodulatory activity and inhibitory effect on tumor growth. Oncotarget. 2015;6(19):17777-79.

  14. Jiao C, Xie YZ, Yang X, Li H, Li XM, Pan HH, Cai MH, Zhong HM, Yang BB. Anticancer activity of Amauroderma rude. PLoS One. 2013;8:e66504.

  15. Poliseno L, Salmena L, Zhang J, Carver B, Haveman WJ, Pandolfi PP. A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature. 2010;465:1033-8.

  16. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495:384-8.

  17. Kumar MS, Armenteros-Monterroso E, East P, Chakravorty P, Matthews N, Winslow MM, Downward J. HMGA2 functions as a competing endogenous RNA to promote lung cancer progression. Nature. 2014;505:212-7.

  18. Anderson MJ, Viars CS, Czekay S, Cavenee WK, Arden KC. Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily. Genomics. 1998;47:187-99.

  19. Salazar M, Lorente M, Garda-Taboada E, Perez Gomez E, Davila D, Zuniga-Garda P, Maria Flores J, Rodriguez A, Hegedus Z, Mosen-Ansorena D, Aransay AM, Hernandez-Tiedra S, Lopez-Valero I, Quintanilla M, Sanchez C, Iovanna JL, Dusetti N, Guzman M, Francis SE, Carracedo A, Kiss-Toth E, Velasco G. Loss of Tribbles pseudokinase-3 promotes Akt-driven tumorigenesis via FOXO inactivation. Cell Death Differ. 2015;22:131-44.

  20. Bowman A, Nusse R. Location, location, location: FOXM1 mediates beta-catenin nuclear translocation and promotes glioma tumorigenesis. Cancer Cell. 2011;20:415-6.

  21. Nestal de Moraes G, Bella L, Zona S, Burton MJ, Lam EW. Insights into a critical role of the FOXO3a-FOXM1 axis in DNA damage response and genotoxic drug resistance. Curr Drug Targets.2014;15:1-14.

  22. Sykes SM, Lane SW, Bullinger L, Kalaitzidis D, Yusuf R, Saez B, Ferraro F, Mercier F, Singh H, Brumme KM, Acharya SS, Scholl C, Tothova Z, Attar EC, Frohling S, DePinho RA, Armstrong SA, Gilliland DG, Scadden DT. AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell. 2011;146:697-708.

  23. Burgering BM, Kops GJ. Cell cycle and death control: long live Forkheads. Trends Biochem Sci. 2002;27(7):352-60.

  24. Myatt SS, Lam EW. The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 2007;7:847-59.

  25. Lin CH, Chang CY, Lee KR, Lin HJ, Chen TH, Wan L. Flavones inhibit breast cancer proliferation through the Akt/FOXO3a signaling pathway. BMC Cancer. 2015;15:958.

  26. Ananda Sadagopan SK, Mohebali N, Looi CY, Hasanpourghadi M, Pandurangan AK, Arya A, Karimian H, Mustafa MR. Forkhead Box Transcription Factor (FOXO3a) mediates the cytotoxic effect of vernodalin in vitro and inhibits the breast tumor growth in vivo. J Exp Clin Cancer Res. 2015;34:147.

  27. Rutnam ZJ, Du WW, Yang W, Yang X, Yang BB. The pseudogene TUSC2P promotes TUSC2 function by binding multiple microRNAs. Nat Commun. 2014;5:2914.

  28. Li H, Gupta S, Du WW, Yang BB. MicroRNA-17 inhibits tumor growth by stimulating T-cell mediated host immune response. Oncoscience. 2014;1:531-9.

  29. Fang L, Du WW, Yang W, Rutnam ZJ, Peng C, Li H, O'Malley YQ, Askeland RW, Sugg S, Liu M, Mehta T, Deng Z, Yang BB. MiR-93 enhances angiogenesis and metastasis by targeting LATS2. Cell Cycle. 2012;11:4352-65.

  30. Monsalve M, Olmos Y, Ersahin T. The complex biology of FOXO. Curr Drug Targets. 2011;12(9):1322-50.

  31. Ersahin T, Tuncbag N, Cetin-Atalay R. The PI3K/AKT/mTOR interactive pathway. Mol Biosyst. 2015;11(7):1946-54.

  32. Lu H, Kyo E, Uesaka T, Katoh O, Watanabe H. Prevention of development of N, N'-dimethylhydrazine-induced colon tumors by a water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi) mycelia in male ICR mice. Int J Mol Med. 2002;9:113-7.

  33. Lu H, Kyo E, Uesaka T, Katoh O, Watanabe H. A water-soluble extract from cultured medium of Ganoderma lucidum (Reishi) mycelia suppresses azoxymethane-induction of colon cancers in male F344 rats. Oncol Rep. 2003;10:375-9.

  34. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261-74.

  35. Wu Y, Peng H, Cui M, Whitney NP, Huang Y, Zheng JC. CXCL12 increases human neural progenitor cell proliferation through Akt-1/FOXO3a signaling pathway. J Neurochem. 2009;109:1157-67.

  36. Das TP, Suman S, Alatassi H, Ankem MK, Damodaran C. Inhibition of AKT promotes FOXO3a-dependent apoptosis in prostate cancer. Cell Death Dis. 2016;7:e2111.

  37. Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY, Zou Y, Bao S, Hanada N, Saso H, Kobayashi R, Hung MC. Ikap-paB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell. 2004;117:225-37.

  38. Yang JY, Zong CS, Xia W, Yamaguchi H, Ding Q, Xie X, Lang JY, Lai CC, Chang CJ, Huang WC, Huang H, Kuo HP, Lee DF, Li LY, Lien HC, Cheng X, Chang KJ, Hsiao CD, Tsai FJ, Tsai CH, Sahin AA, Muller WJ, Mills GB, Yu D, Hortobagyi GN, Hung MC. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol. 2008;10:138-48.

  39. Leroy C, Ramos P, Cornille K, Bonenfant D, Fritsch C, Voshol H, Bentires-Alj M. Activation of IGF1R/p110beta/AKT/ mTOR confers resistance to alpha-specific PI3K inhibition. Breast Cancer Res. 2016;18:41.

  40. Zhang XL, Zhuang TT, Liang ZY, Li L, Xue ML, Liu J, Liang H. Breast cancer suppression by aplysin is associated with inhibition of PI3K/AKT/FOXO3a pathway. Oncotarget. 2017;8(38):63923-34.

  41. Taylor S, Lam M, Pararasa C, Brown JE, Carmichael AR, Griffiths HR. Evaluating the evidence for targeting FOXO3a in breast cancer: a systematic review. Cancer Cell Int. 2015;15:1.

  42. Dobson M, Ramakrishnan G, Ma S, Kaplun L, Balan V, Fridman R, Tzivion G. Bimodal regulation of FOXO3 by AKT and 14-3-3. Biochim Biophys Acta. 2011;1813:1453-64.

  43. Hauck L, Harms C, Grothe D, An J, Gertz K, Kronenberg G, Dietz R, Endres M, von Harsdorf R. Critical role for FOXO3a-dependent regulation of p21CIP1/WAF1 in response to statin signaling in cardiac myocytes. Circ Res. 2007;100:50-60.

  44. Chandramohan V, Mineva ND, Burke B, Jeay S, Wu M, Shen J, Yang W, Hann SR, Sonenshein GE. c-Myc represses FOXO3a-mediated transcription of the gene encoding the p27(Kip1) cyclin dependent kinase inhibitor. J Cell Biochem. 2008;104:2091-106.

  45. Cho EC, Kuo ML, Liu X, Yang L, Hsieh YC, Wang J, Cheng Y, Yen Y. Tumor suppressor FOXO3 regulates ribonucleotide reductase subunit RRM2B and impacts on survival of cancer patients. Oncotarget. 2014;5:4834-44.

  46. Nakao T, Geddis AE, Fox NE, Kaushansky K. PI3K/Akt/FOXO3a pathway contributes to thrombopoietin-induced proliferation of primary megakaryocytes in vitro and in vivo via modulation of p27(Kip1). Cell Cycle. 2008;7:257-66.

  47. Andres-Pons A, Gil A, Oliver MD, Sotelo NS, Pulido R. Cytoplasmic p27Kip1 counteracts the pro-apoptotic function of the open conformation of PTEN by retention and destabilization of PTEN outside of the nucleus. Cell Signal. 2012;24:577-87.

  48. Yang DS, Gao X, Ye ZM, Tao HM, Li WX. Induction of apoptosis and accumulation of p27 (Kip1) protein by proteasome inhibitor MG132 in human osteosarcoma MG63 cells. Chin J Orthop (Chin). 2005;25:613-7.

  49. Xie QX, Han CX, Lin FD, Meng JR. Clinical signifi cance of p27 expression in blandder cancer. Chin J Mod Med (Chin). 2002;18:19-21.

  50. Barnes A, Pinder SE, Bell JA, Paish EC, Wencyk PM, Robertson JF, Elston CW, Ellis IO. Expression of p27 kip1 in breast cancer and its prognostic signifi cance. J Pathol. 2003;201:451-9.

Articles with similar content:

Evaluation of LncRNA ANRIL Potential in Hepatic Cancer Progression
Journal of Environmental Pathology, Toxicology and Oncology, Vol.38, 2019, issue 2
Yong Wang, Wanhua Ren, Zhaoyang Guo, Haiqing Liang, Hao Sun, Meili Lu, Yongjian Ji, Zhuozhen Lv
KLF4 in Ovarian Cancer
Onco Therapeutics, Vol.7, 2016, issue 1-2
Lawrence M. Pfeffer, Baojin Wang, Ziyun Du, Junming Yue
(−)-Epigallocatechin-3-gallate inhibits osteosarcoma cell invasiveness by inhibiting the MEK/ERK signaling pathway in human osteosarcoma cells
Journal of Environmental Pathology, Toxicology and Oncology, Vol.34, 2015, issue 1
Zhengshi Zhang, Yong Wang, Guoqing Tang, Hongbin Qian, Bin Chen, Ji Chen, Yong Chen, Xiang Chen
Epidemiological and Clinical Aspects of Nonsteroidal Anti-inflammatory Drugs and Cancer Risks
Journal of Environmental Pathology, Toxicology and Oncology, Vol.21, 2002, issue 2
Edgar M. Moran
Autophagy Inhibition Enhances SPCA-1 Cell Proliferation Inhibition Induced by By-1 from the Stout Camphor Medicinal Mushroom, Taiwanofungus camphoratus (Agaricomycetes)
International Journal of Medicinal Mushrooms, Vol.20, 2018, issue 4
Di Wu, Wenbo Sun, Yanfang Liu, Yaping Zhang, Yan Yang, Li Min, Hairui Yang, Zheng Qiankun, Wei Jia, Wenhan Wang, Jinsong Zhang