eISSN: 1896-9151
ISSN: 1734-1922
Archives of Medical Science
Current issue Archive Manuscripts accepted About the journal Special issues Editorial board Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank
6/2018
vol. 14
 
Share:
Share:
more
 
 
abstract:
Basic research

Inositol-6 phosphate inhibits the mTOR pathway and induces autophagy-mediated death in HT-29 colon cancer cells

Ashok Kumar Pandurangan, Salmiah Ismail, Norhaizan Mohd Esa, Murugan A. Munusamy

Arch Med Sci 2018; 14, 6: 1281–1288
Online publish date: 2018/07/05
View full text
Get citation
ENW
EndNote
BIB
JabRef, Mendeley
RIS
Papers, Reference Manager, RefWorks, Zotero
AMA
APA
Chicago
Harvard
MLA
Vancouver
 
Introduction
Colorectal cancer (CRC) is common, with a worldwide incidence estimated at more than 1 million cases annually. Therefore, the search for agents for CRC treatment is highly warranted. Inositol-6 phosphate (IP6) is enriched in rice bran and possesses many beneficial effects. Mammalian target of rapamycin (mTOR) is a vital signaling pathway involved in many cellular processes. Inhibition of the mTOR pathway leads to the activation of autophagy-mediated cell death. Autophagy is a cell survival process as well as a cell death mechanism and is a response to various anticancer therapies in cancer cell types. We studied the effect of IP6 on autophagy-mediated death in HT-29 colon cancer cells.

Material and methods
Autophagy was assessed by acridine orange (AO) staining, transmission electron microscopy, and western blotting to detect LC3-II and Beclin 1. Akt/mTOR signaling protein expression was also analyzed by western blotting. Apoptosis was analyzed by annexin V staining.

Results
Incubation of cells with IP6 resulted in downregulation of the p-Akt and mTOR pathway in a time-dependent manner. Inositol-6 phosphate (10 µg/ml, 24 and 48 h) induced autophagic vesicles, as confirmed by AO staining and transmission electron microscopy. We also found increased expression of LC3-II and Beclin 1 in a time-dependent manner after incubation with IP6. Furthermore, IP6 induced apoptosis, as revealed by annexin V staining.

Conclusion
Our results clearly indicate that IP6 induces autophagy by inhibiting the Akt/mTOR pathway.

keywords:

inositol-6-phosphate, colorectal cancer, autophagy, mammalian target of rapamycin (mTOR), apoptosis

references:
Huerta S, Goulet EJ, Livingston EH. Colon cancer and apoptosis. Am J Surg 2006; 191: 517-26.
Sheng WY, Yong Z, Yun Z, Hong H, Hai LL. Toll-like receptor 4 gene polymorphisms and susceptibility to colorectal cancer: a meta-analysis and review. Arch Med Sci 2015; 11: 699-707.
Pandurangan AK, Esa NM. Dietary non-nutritive factors in targeting of regulatory molecules in colorectal cancer: an update. Asian Pac J Cancer Prev 2013; 14: 5543-52.
Pandurangan AK, Dharmalingam P, Sadagopan SK, Ganapasam S. Luteolin inhibits matrix metalloproteinase 9 and 2 in azoxymethane-induced colon carcinogenesis. Hum Exp Toxicol 2014; 33: 1176-85.
Saadatdoust Z, Pandurangan AK, Ananda Sadagopan SK, Mohd Esa N, Ismail A, Mustafa MR. Dietary cocoa inhibits colitis associated cancer: a crucial involvement of the IL-6/STAT3 pathway. J Nutr Biochem 2015; 26: 1547-58.
Ananda Sadagopan SK, Mohebali N, Looi CY, et al. 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.
Wu D, Yao Q, Chen Y, Hu X, Qing C, Qiu M. The in Vitro and in Vivo Antitumor Activities of Tetracyclic Triterpenoids Compounds Actein and 26-Deoxyactein Isolated from Rhizome of Cimicifuga foetida L. Molecules 2016; 21: E1001.
Lai YJ, Tai CJ, Wang CW, et al. Anti-Cancer Activity of Solanum nigrum (AESN) through Suppression of Mitochondrial Function and Epithelial-Mesenchymal Transition (EMT) in Breast Cancer Cells. Molecules 2016; 21: E553.
Jariwalla RJ. Rice-bran products: phytonutrients with potential applications in preventive and clinical medicine. Drugs Exp Clin Res 2001; 27: 17-26.
Shamsuddin AM. Anti-cancer function of phytic acid. Int J Food Sci Technol 2002; 37: 769-82.
Norazalina S, Norhaizan ME, Hairuszah I, Norashareena MS. Anticarcinogenic efficacy of phytic acid extracted from rice bran on azoxymethane-induced colon carcinogenesis in rats. Exp Toxicol Pathol 2010; 62: 259-68.
Nurul-Husna S, Norhaizan ME, Hairuszah I, Abdah MA, Norazalina S, Norsharina I. Rice bran phytic acid (IP6) induces growth inhibition, cell cycle arrest and apoptosis on human colorectal adenocarcinoma cells. J Med Plants Res 2010; 4: 2283-9.
Norazalina S, Norhaizan ME, Hairuszah I, Sabariah AR, Husna SN, Norsharina I. Antiproliferation and apoptosis induction of phytic acid in hepatocellular carcinoma (HEPG 2) cell lines. Afr J Biotechnol 2011; 10: 16646-53.
Wani ZA, Guru SK, Rao AV, et al. A novel quinazolinone chalcone derivative induces mitochondrial dependent apoptosis and inhibits PI3K/Akt/mTOR signaling pathway in human colon cancer HCT-116 cells. Food Chem Toxicol 2016; 87: 1-11.
Wee LH, Morad NA, Aan GJ, Makpol S, Wan Ngah WZ, Mohd Yusof YA. Mechanism of Chemoprevention against Colon Cancer Cells Using Combined Gelam Honey and Ginger Extract via mTOR and Wnt/beta-catenin Pathways. Asian Pac J Cancer Prev 2015; 16: 6549-56.
Din FV, Valanciute A, Houde VP, et al. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 2012; 142: 1504-15.e3.
Lin L, Baehrecke EH. Autophagy, cell death, and cancer. Mol Cell Oncol 2015; 2: e985913.
Chan WY, Huang H, Tam SC. Receptor-mediated endocytosis of trichosanthin in choriocarcinoma cells. Toxicology 2003; 186: 191-203.
Pandurangan AK, Dharmalingam P, Sadagopan SK, Ramar M, Munusamy A, Ganapasam S. Luteolin induces growth arrest in colon cancer cells through involvement of Wnt/beta-catenin/GSK-3beta signaling. J Environ Pathol Toxicol Oncol 2013; 32: 131-9.
Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007; 12: 9-22.
Pullen N, Thomas G. The modular phosphorylation and activation of p70s6k. FEBS Lett 1997; 410: 78-82.
Towers CG, Thorburn A. Therapeutic Targeting of Autophagy. EBioMedicine 2016; 14: 15-23.
Klionsky DJ, Abeliovich H, Agostinis P, et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 2008; 4: 151-75.
Zhang C, Yu H, Shen Y, Ni X, Shen S, Das UN. Polyunsaturated fatty acids trigger apoptosis of colon cancer cells through a mitochondrial pathway. Arch Med Sci 2015; 11: 1081-94.
Irani S, Shahmirani Z, Atyabi SM, Mirpoor S. Induction of growth arrest in colorectal cancer cells by cold plasma and gold nanoparticles. Arch Med Sci 2015; 11: 1286-95.
Lai MD, Xu J. Ribosomal proteins and colorectal cancer. Curr Genomics 2007; 8: 43-9.
Pandurangan AK. Potential targets for prevention of colorectal cancer: a focus on PI3K/Akt/mTOR and Wnt pathways. Asian Pac J Cancer Prev 2013; 14: 2201-5.
Fujishita T, Aoki K, Lane HA, Aoki M, Taketo MM. Inhibition of the mTORC1 pathway suppresses intestinal polyp formation and reduces mortality in ApcDelta716 mice. Proc Natl Acad Sci U S A 2008; 105: 13544-9.
Din FV, Valanciute A, Houde VP, et al. Aspirin inhibits mTOR signaling, activates AMP-activated protein kinase, and induces autophagy in colorectal cancer cells. Gastroenterology 2012; 142: 1504-15.e3.
Wu J, Hu G, Dong Y, et al. Matrine induces Akt/mTOR signalling inhibition-mediated autophagy and apoptosis in acute myeloid leukaemia cells. J Cell Mol Med 2017; 21: 1171-81.
Parkhitko AA, Favorova OO, Henske EP. Autophagy: mechanisms, regulation, and its role in tumorigenesis. Biochemistry (Mosc) 2013; 78: 355-67.
Suh Y, Afaq F, Khan N, Johnson JJ, Khusro FH, Mukhtar H. Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis 2010; 31: 1424-33.
Lee Y, Sung B, Kang YJ, et al. Apigenin-induced apoptosis is enhanced by inhibition of autophagy formation in HCT116 human colon cancer cells. Int J Oncol 2014; 44: 1599-606.
Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell 2010; 140: 313-26.
Shafie NH, Esa NM, Ithnin H, Saad N, Pandurangan AK. Pro-apoptotic effect of rice bran inositol hexaphosphate (IP6) on HT-29 colorectal cancer cells. Int J Mol Sci 2013; 14: 23545-58.
Shafie NH, Mohd Esa N, Ithnin H, Md Akim A, Saad N, Pandurangan AK. Preventive inositol hexaphosphate extracted from rice bran inhibits colorectal cancer through involvement of Wnt/beta-catenin and COX-2 pathways. Biomed Res Int 2013; 2013: 681027.
FEATURED PRODUCTS
Quick links
© 2018 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe