Effect of Alkylresorcinols on Autophagy, Migration, and Invasion of HepG2 Cells.

Alkylresorcinols are phenolic lipids that mainly exist in the cortex of grains, and they exhibit anticancer activity against various cancer cells in vitro. However, the underlying action mechanisms are still unclear. In our study, the influence of alkylresorcinols C19:0 and C21:0 (ARs) upon migration, invasion, and autophagy in human hepatoblastoma HepG2 cells was evaluated. Results showed that ARs at 80 and 160 µg/mL significantly suppressed cells proliferation, migration, and invasion, downregulated the expression of proteins RhoA and MMP-7 associated with migration and invasion. ARs at 160 µg/mL, the rate of LC3 puncta was appreciably increased. After autophagy was blocked by 3-MA or CQ, the expression of LC3II was significantly increased in 3-MA+ARs group and p62 was significantly decreased in CQ+ARs group. The results indicate that ARs may promote autophagic flow. ARs (80, 160 µg/mL) significantly inhibited the expression of proteins p-mTOR, p-PI3K, and p-Akt related to the PI3K/Akt pathway. The results of the present study suggest that ARs can activate autophagy and suppresses the biological behaviors of HepG2 cells by inhibiting the activation of MMP-7, Rho/Rho-associated protein kinase, and activation of the phosphatidylinositol 3-kinase/Akt signaling pathway. PRACTICAL APPLICATION: The anticancer mechanism of ARs in wheat bran was studied, which provided a basis for the development of anticancer functional auxiliary food with wheat bran as raw material. It is of great practical significance to promote the effective utilization of grain processing by-products and improve the economic benefits of the grain industry.

[1]  Jing Li,et al.  Flavonoids inhibit cell proliferation and induce apoptosis and autophagy through downregulation of PI3Kγ mediated PI3K/AKT/mTOR/p70S6K/ULK signaling pathway in human breast cancer cells , 2018, Scientific Reports.

[2]  R. Panhwar,et al.  Phytochemical Components of Some Minor Cereals Associated with Diabetes Prevention and Management , 2018 .

[3]  Xiao-Ming Yang,et al.  Effects of ginkgol C17:1 on cisplatin-induced autophagy and apoptosis in HepG2 cells , 2017, Oncology letters.

[4]  Chunhua Wang,et al.  Anticancer activities of harmine by inducing a pro-death autophagy and apoptosis in human gastric cancer cells. , 2017, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[5]  Xiao-Ming Yang,et al.  Inhibitory effect of Ginkgol C17:1 on the biological behavior of tumor cells , 2017, Oncology letters.

[6]  Xu Li,et al.  Ginsenoside 20(S)-Rg3 induced autophagy to inhibit migration and invasion of ovarian cancer. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[7]  D. Tierney,et al.  Biochemical characterization and zinc binding group (ZBGs) inhibition studies on the catalytic domain of MMP7 (cdMMP7). , 2016, Journal of inorganic biochemistry.

[8]  Jin-jian Lu,et al.  Chikusetsusaponin IVa methyl ester induces G1 cell cycle arrest, triggers apoptosis and inhibits migration and invasion in ovarian cancer cells. , 2016, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[9]  M. Arlorio,et al.  Alkylresorcinol content in whole grains and pearled fractions of wheat and barley , 2016 .

[10]  Yingyu Cui,et al.  Effects of Pinus massoniana bark extract on the invasion capability of HeLa cells , 2016 .

[11]  Mu-Kuan Chen,et al.  Glabridin induces apoptosis and autophagy through JNK1/2 pathway in human hepatoma cells. , 2016, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[12]  R. Landberg,et al.  Determination of alkylresorcinols and their metabolites in biological samples by gas chromatography-mass spectrometry. , 2015, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[13]  F. Sinicrope,et al.  p62/Sequestosome-1 Up-regulation Promotes ABT-263-induced Caspase-8 Aggregation/Activation on the Autophagosome* , 2013, The Journal of Biological Chemistry.

[14]  Zachary C. Dobbin,et al.  The Importance of the PI3K/AKT/MTOR Pathway in the Progression of Ovarian Cancer , 2013, International journal of molecular sciences.

[15]  Quentin Liu,et al.  Low expression of Beclin 1 and elevated expression of HIF-1α refine distant metastasis risk and predict poor prognosis of ER-positive, HER2-negative breast cancer , 2013, Medical Oncology.

[16]  Lei Liu,et al.  Wheat bran lipophilic compounds with in vitro anticancer effects , 2012 .

[17]  S. Sang,et al.  5-alk(en)ylresorcinols as the major active components in wheat bran inhibit human colon cancer cell growth. , 2011, Bioorganic & medicinal chemistry.

[18]  Meuillet Ej Novel inhibitors of AKT: assessment of a different approach targeting the pleckstrin homology domain. , 2011 .

[19]  G. Bjørkøy,et al.  p62/SQSTM1 Binds Directly to Atg8/LC3 to Facilitate Degradation of Ubiquitinated Protein Aggregates by Autophagy* , 2007, Journal of Biological Chemistry.

[20]  P. Codogno,et al.  Autophagy and signaling: their role in cell survival and cell death , 2005, Cell Death and Differentiation.

[21]  Adolfo Saiardi,et al.  Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphate results in antiangiogenic and antitumor effects. , 2005, Cancer research.

[22]  P. Åman,et al.  Chromatographic analysis of alkylresorcinols and their metabolites. , 2004, Journal of chromatography. A.

[23]  P. Galle,et al.  Cleavage of CD95 by matrix metalloproteinase-7 induces apoptosis resistance in tumour cells , 2004, Oncogene.

[24]  K. Yano,et al.  Matrix Metalloproteinase-7 Facilitates Insulin-Like Growth Factor Bioavailability through Its Proteinase Activity on Insulin-Like Growth Factor Binding Protein 3 , 2004, Cancer Research.

[25]  P. Åman,et al.  Alkylresorcinols in cereals and cereal products. , 2003, Journal of agricultural and food chemistry.

[26]  H. Yamamoto,et al.  Clinicopathologic and prognostic significance of matrilysin expression at the invasive front in human colorectal cancers , 2001, International journal of cancer.

[27]  A. Kulma,et al.  Impact of four antimutagens on apoptosis in genotoxically damaged lymphocytes in vitro. , 2001, Cellular & molecular biology letters.

[28]  S. Hecht,et al.  Naturally occurring alkylresorcinols that mediate DNA damage and inhibit its repair. , 2000, Biochemistry.

[29]  L. M. Seitz Identification of 5-(2-oxoalkyl)resorcinols and 5-(2-oxoalkenyl)resorcinols in wheat and rye grains , 1992 .

[30]  A. Salomonsson,et al.  Analysis of alkyl‐ and alkenylresorcinols in triticale, wheat and rye , 1988 .

[31]  J. Tyman Determination of the component phenols in natural and technical cashew nut-shell liquid by gas-liquid chromatography , 1976 .

[32]  E. M. Wilson,et al.  Wheat Bran Phenols1 , 1964 .