Skip to main content
Top
Published in: BMC Complementary Medicine and Therapies 1/2021

Open Access 01-12-2021 | Gastric Cancer | Research article

Procyanidin B2 induces apoptosis and autophagy in gastric cancer cells by inhibiting Akt/mTOR signaling pathway

Authors: Yuqin Li, Xiaolan Lu, Peiying Tian, Kai Wang, Jianping Shi

Published in: BMC Complementary Medicine and Therapies | Issue 1/2021

Login to get access

Abstract

Background

Procyanidin B2 (PB2), a unique component of the grape seed and other medicinal plants. PB2 has shown wide anticancer activity in various human cancer cells. However, it remains unclear about the biological effects and associated mechanisms of PB2 on gastric cancer cells.

Methods

Cell proliferation was measured by CCK8 assay, and cellular lactate dehydrogenase (LDH) release was measured in the culture medium. Cellular apoptosis was observed via TUNEL staining assay and measured by caspase-3 and -9 activities. Autophagy was observed by LC3 staining. Western blot analysis was performed to verify autophagy-associated proteins (Beclin1 and Atg5) and Akt-mTOR pathway.

Results

PB2 reduced the viability of BGC-823 and SGC-7901 cells in a concentration-dependent manner. Furthermore, PB2 induced increased apoptosis rate of gastric cancer cells and enhanced caspase-3 and -9 activities. Simultaneously, PB2 triggered autophagy in gastric cancer cells, with enhanced LC3 staining and increased expression of Beclin1 and Atg5, while the inhibition of autophagy by 3-MA reversed the PB2-induced suppression on cell viability. In addition, PB2 significantly decreased p-Akt and p-mTOR protein expression of gastric cancer cells.

Conclusion

PB2 exerts anti-proliferative and apoptotic effects and induces autophagy by modulating Akt/mTOR signaling pathway. PB2 may be developed as a potential therapeutic drug for gastric cancer.
Literature
1.
go back to reference Lin X, Zhao Y, Song WM, Zhang B. Molecular classification and prediction in gastric cancer. Comput Struct Biotechnol J. 2015;13:448–58.CrossRef Lin X, Zhao Y, Song WM, Zhang B. Molecular classification and prediction in gastric cancer. Comput Struct Biotechnol J. 2015;13:448–58.CrossRef
2.
go back to reference Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.CrossRef Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.CrossRef
3.
go back to reference Kim IH. Current status of adjuvant chemotherapy for gastric cancer. World J Gastrointest Oncol. 2019;11(9):679–85.CrossRef Kim IH. Current status of adjuvant chemotherapy for gastric cancer. World J Gastrointest Oncol. 2019;11(9):679–85.CrossRef
4.
go back to reference Shi WJ, Gao JB. Molecular mechanisms of chemoresistance in gastric cancer. World J Gastrointest Oncol. 2016;8(9):673–81.CrossRef Shi WJ, Gao JB. Molecular mechanisms of chemoresistance in gastric cancer. World J Gastrointest Oncol. 2016;8(9):673–81.CrossRef
5.
go back to reference Su Z, Yang Z, Xu Y, Chen Y, Yu Q. Apoptosis, autophagy, necroptosis, and cancer metastasis. Mol Cancer. 2015;14:48.CrossRef Su Z, Yang Z, Xu Y, Chen Y, Yu Q. Apoptosis, autophagy, necroptosis, and cancer metastasis. Mol Cancer. 2015;14:48.CrossRef
6.
7.
go back to reference Levin-Salomon V, Bialik S, Kimchi A. DAP-kinase and autophagy. Apoptosis. 2014;19(2):346–56.CrossRef Levin-Salomon V, Bialik S, Kimchi A. DAP-kinase and autophagy. Apoptosis. 2014;19(2):346–56.CrossRef
8.
go back to reference Wei F, Jiang X, Gao HY, Gao SH. Liquiritin induces apoptosis and autophagy in cisplatin (DDP)-resistant gastric cancer cells in vitro and xenograft nude mice in vivo. Int J Oncol. 2017;51(5):1383–94.CrossRef Wei F, Jiang X, Gao HY, Gao SH. Liquiritin induces apoptosis and autophagy in cisplatin (DDP)-resistant gastric cancer cells in vitro and xenograft nude mice in vivo. Int J Oncol. 2017;51(5):1383–94.CrossRef
9.
go back to reference Li Y, Liu Y, Shi F, Cheng L, She J. Knockdown of Rap1b enhances apoptosis and autophagy in gastric Cancer cells via the PI3K/Akt/mTOR pathway. Oncol Res. 2016;24(5):287–93.CrossRef Li Y, Liu Y, Shi F, Cheng L, She J. Knockdown of Rap1b enhances apoptosis and autophagy in gastric Cancer cells via the PI3K/Akt/mTOR pathway. Oncol Res. 2016;24(5):287–93.CrossRef
10.
go back to reference Lu R, Zhao G, Yang Y, Jiang Z, Cai J, Hu H. Inhibition of CD133 overcomes Cisplatin resistance through inhibiting PI3K/AKT/mTOR signaling pathway and autophagy in CD133-positive gastric Cancer cells. Technol Cancer Res Treat. 2019;18:1533033819864311.CrossRef Lu R, Zhao G, Yang Y, Jiang Z, Cai J, Hu H. Inhibition of CD133 overcomes Cisplatin resistance through inhibiting PI3K/AKT/mTOR signaling pathway and autophagy in CD133-positive gastric Cancer cells. Technol Cancer Res Treat. 2019;18:1533033819864311.CrossRef
11.
go back to reference Li C, Wang Y, Wang C, Yi X, Li M, He X. Anticancer activities of harmine by inducing a pro-death autophagy and apoptosis in human gastric cancer cells. Phytomedicine. 2017;28:10–8.CrossRef Li C, Wang Y, Wang C, Yi X, Li M, He X. Anticancer activities of harmine by inducing a pro-death autophagy and apoptosis in human gastric cancer cells. Phytomedicine. 2017;28:10–8.CrossRef
12.
go back to reference Li W, Zhou Y, Yang J, Li H, Zhang H, Zheng P. Curcumin induces apoptotic cell death and protective autophagy in human gastric cancer cells. Oncol Rep. 2017;37(6):3459–66.CrossRef Li W, Zhou Y, Yang J, Li H, Zhang H, Zheng P. Curcumin induces apoptotic cell death and protective autophagy in human gastric cancer cells. Oncol Rep. 2017;37(6):3459–66.CrossRef
13.
go back to reference Lee HJ, Venkatarame Gowda Saralamma V, Kim SM, Ha SE, Raha S, Lee WS, et al. Pectolinarigenin Induced Cell Cycle Arrest, Autophagy, and Apoptosis in Gastric Cancer Cell via PI3K/AKT/mTOR Signaling Pathway. Nutrients. 2018;10(8). pii: E1043. Lee HJ, Venkatarame Gowda Saralamma V, Kim SM, Ha SE, Raha S, Lee WS, et al. Pectolinarigenin Induced Cell Cycle Arrest, Autophagy, and Apoptosis in Gastric Cancer Cell via PI3K/AKT/mTOR Signaling Pathway. Nutrients. 2018;10(8). pii: E1043.
14.
go back to reference Huang Y, Chen X, Guo G, Guo W, Ma Q, Yuan J. Sophocarpine inhibits the growth of gastric cancer cells via autophagy and apoptosis. Front Biosci (Landmark Ed). 2019;24:616–27.CrossRef Huang Y, Chen X, Guo G, Guo W, Ma Q, Yuan J. Sophocarpine inhibits the growth of gastric cancer cells via autophagy and apoptosis. Front Biosci (Landmark Ed). 2019;24:616–27.CrossRef
15.
go back to reference Li JH, Zhang SW, Liu J, Shao MZ, Chen L. Review of clinical investigation on recurrence of gastric cancer following curative resection. Chin Med J. 2012;125(8):1479–95.PubMed Li JH, Zhang SW, Liu J, Shao MZ, Chen L. Review of clinical investigation on recurrence of gastric cancer following curative resection. Chin Med J. 2012;125(8):1479–95.PubMed
16.
go back to reference de Pascual-Teresa S, Moreno DA, García-Viguera C. Flavanols and anthocyanins in cardiovascular health: a review of current evidence. Int J Mol Sci. 2010;11(4):1679–703.CrossRef de Pascual-Teresa S, Moreno DA, García-Viguera C. Flavanols and anthocyanins in cardiovascular health: a review of current evidence. Int J Mol Sci. 2010;11(4):1679–703.CrossRef
17.
go back to reference Yang H, Xiao L, Yuan Y, Luo X, Jiang M, Ni J, et al. Procyanidin B2 inhibits NLRP3 inflammasome activation in human vascular endothelial cells. Biochem Pharmacol. 2014;92(4):599–606.CrossRef Yang H, Xiao L, Yuan Y, Luo X, Jiang M, Ni J, et al. Procyanidin B2 inhibits NLRP3 inflammasome activation in human vascular endothelial cells. Biochem Pharmacol. 2014;92(4):599–606.CrossRef
18.
go back to reference Chuang CC, McIntosh MK. Potential mechanisms by which polyphenol-rich grapes prevent obesity-mediated inflammation and metabolic diseases. Annu Rev Nutr. 2011;31:155–76.CrossRef Chuang CC, McIntosh MK. Potential mechanisms by which polyphenol-rich grapes prevent obesity-mediated inflammation and metabolic diseases. Annu Rev Nutr. 2011;31:155–76.CrossRef
19.
go back to reference Mackenzie GG, Adamo AM, Decker NP, Oteiza PI. Dimeric procyanidin B2 inhibits constitutively active NF-kappaB in Hodgkin's lymphoma cells independently of the presence of IkappaB mutations. Biochem Pharmacol. 2008;75(7):1461–71.CrossRef Mackenzie GG, Adamo AM, Decker NP, Oteiza PI. Dimeric procyanidin B2 inhibits constitutively active NF-kappaB in Hodgkin's lymphoma cells independently of the presence of IkappaB mutations. Biochem Pharmacol. 2008;75(7):1461–71.CrossRef
20.
go back to reference Avelar MM, Gouvêa CM. Procyanidin b2 cytotoxicity to mcf-7 human breast adenocarcinoma cells. Indian J pharm Sci. 2012;74(4):351-5. Gopalakrishnan S, Ediga HH, Reddy SS, Reddy GB, Ismail a. Procyanidin-B2 enriched fraction of cinnamon acts as a proteasome inhibitor and anti-proliferative agent in human prostate cancer cells. IUBMB Life. 2018;70(5):445–57.CrossRef Avelar MM, Gouvêa CM. Procyanidin b2 cytotoxicity to mcf-7 human breast adenocarcinoma cells. Indian J pharm Sci. 2012;74(4):351-5. Gopalakrishnan S, Ediga HH, Reddy SS, Reddy GB, Ismail a. Procyanidin-B2 enriched fraction of cinnamon acts as a proteasome inhibitor and anti-proliferative agent in human prostate cancer cells. IUBMB Life. 2018;70(5):445–57.CrossRef
21.
go back to reference Gopalakrishnan S, Ediga HH, Reddy SS, Reddy GB, Ismail A. Procyanidin-B2 enriched fraction of cinnamon acts as a proteasome inhibitor and anti-proliferative agent in human prostate cancer cells. IUBMB Life. 2018;70(5):445–57.CrossRef Gopalakrishnan S, Ediga HH, Reddy SS, Reddy GB, Ismail A. Procyanidin-B2 enriched fraction of cinnamon acts as a proteasome inhibitor and anti-proliferative agent in human prostate cancer cells. IUBMB Life. 2018;70(5):445–57.CrossRef
22.
go back to reference Shilpi A, Parbin S, Sengupta D, Kar S, Deb M, Rath SK, et al. Mechanisms of DNA methyltransferase-inhibitor interactions: Procyanidin B2 shows new promise for therapeutic intervention of cancer. Chem Biol Interact. 2015;233:122–38.CrossRef Shilpi A, Parbin S, Sengupta D, Kar S, Deb M, Rath SK, et al. Mechanisms of DNA methyltransferase-inhibitor interactions: Procyanidin B2 shows new promise for therapeutic intervention of cancer. Chem Biol Interact. 2015;233:122–38.CrossRef
23.
go back to reference Nomoto H, Iigo M, Hamada H, Kojima S, Tsuda H. Chemoprevention of colorectal cancer by grape seed proanthocyanidin is accompanied by a decrease in proliferation and increase in apoptosis. Nutr Cancer. 2004;49(1):81–8.CrossRef Nomoto H, Iigo M, Hamada H, Kojima S, Tsuda H. Chemoprevention of colorectal cancer by grape seed proanthocyanidin is accompanied by a decrease in proliferation and increase in apoptosis. Nutr Cancer. 2004;49(1):81–8.CrossRef
24.
go back to reference Tyagi A, Kumar S, Raina K, Wempe MF, Maroni PD, Agarwal R, et al. Differential effect of grape seed extract and its active constituent procyanidin B2 3,3″-di-O-gallate against prostate cancer stem cells. Mol Carcinog. 2019;58(7):1105–17.CrossRef Tyagi A, Kumar S, Raina K, Wempe MF, Maroni PD, Agarwal R, et al. Differential effect of grape seed extract and its active constituent procyanidin B2 3,3″-di-O-gallate against prostate cancer stem cells. Mol Carcinog. 2019;58(7):1105–17.CrossRef
25.
go back to reference Feng Y, Xiong Y, Qiao T, Li X, Jia L, Han Y. Lactate dehydrogenase a: a key player in carcinogenesis and potential target in cancer therapy. Cancer Med. 2018;7(12):6124–36.CrossRef Feng Y, Xiong Y, Qiao T, Li X, Jia L, Han Y. Lactate dehydrogenase a: a key player in carcinogenesis and potential target in cancer therapy. Cancer Med. 2018;7(12):6124–36.CrossRef
26.
go back to reference Zhao Z, Han F, Yang S, Hua L, Wu J, Zhan W. The clinicopathologic importance of serum lactic dehydrogenase in patients with gastric cancer. Dis Markers. 2014;2014:140913.CrossRef Zhao Z, Han F, Yang S, Hua L, Wu J, Zhan W. The clinicopathologic importance of serum lactic dehydrogenase in patients with gastric cancer. Dis Markers. 2014;2014:140913.CrossRef
27.
go back to reference Shang H, Cao Z, Zhao J, Guan J, Liu J, Peng J, et al. Babao Dan induces gastric cancer cell apoptosis via regulating MAPK and NF-κB signaling pathways. J Int Med Res. 2019;47(10):5106–19.CrossRef Shang H, Cao Z, Zhao J, Guan J, Liu J, Peng J, et al. Babao Dan induces gastric cancer cell apoptosis via regulating MAPK and NF-κB signaling pathways. J Int Med Res. 2019;47(10):5106–19.CrossRef
28.
go back to reference Endo K, Matsui R, Sugiyama M, Asami T, Inaba C, Kobayashi S, et al. Procyanidin B2 gallate regulates TNF-α production from T cells through inhibiting glycolytic activity via mTOR-HIF-1 pathway. Biochem Pharmacol. 2020;177:113952.CrossRef Endo K, Matsui R, Sugiyama M, Asami T, Inaba C, Kobayashi S, et al. Procyanidin B2 gallate regulates TNF-α production from T cells through inhibiting glycolytic activity via mTOR-HIF-1 pathway. Biochem Pharmacol. 2020;177:113952.CrossRef
29.
go back to reference McIlwain DR, Berger T, Mak TW. Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol. 2013;5(4):a008656.CrossRef McIlwain DR, Berger T, Mak TW. Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol. 2013;5(4):a008656.CrossRef
30.
go back to reference Ramos S, Rodríguez-Ramiro I, Martín MA, Goya L, Bravo L. Dietary flavanols exert different effects on antioxidant defenses and apoptosis/proliferation in Caco-2 and SW480 colon cancer cells. Toxicol in Vitro. 2011;25(8):1771–81.CrossRef Ramos S, Rodríguez-Ramiro I, Martín MA, Goya L, Bravo L. Dietary flavanols exert different effects on antioxidant defenses and apoptosis/proliferation in Caco-2 and SW480 colon cancer cells. Toxicol in Vitro. 2011;25(8):1771–81.CrossRef
31.
go back to reference Al-Shenawy HA. Expression of Beclin-1, an autophagy-related marker, in chronic hepatitis and hepatocellular carcinoma and its relation with apoptotic markers. APMIS. 2016;124(3):229–37.CrossRef Al-Shenawy HA. Expression of Beclin-1, an autophagy-related marker, in chronic hepatitis and hepatocellular carcinoma and its relation with apoptotic markers. APMIS. 2016;124(3):229–37.CrossRef
32.
go back to reference Ge J, Chen Z, Huang J, Chen J, Yuan W, Deng Z, et al. Upregulation of autophagy-related gene-5 (ATG-5) is associated with chemoresistance in human gastric cancer. PLoS One. 2014;9(10):e110293.CrossRef Ge J, Chen Z, Huang J, Chen J, Yuan W, Deng Z, et al. Upregulation of autophagy-related gene-5 (ATG-5) is associated with chemoresistance in human gastric cancer. PLoS One. 2014;9(10):e110293.CrossRef
33.
go back to reference Mukhopadhyay S, Panda PK, Sinha N, Das DN, Bhutia SK. Autophagy and apoptosis: where do they meet? Apoptosis. 2014;19(4):555–66.CrossRef Mukhopadhyay S, Panda PK, Sinha N, Das DN, Bhutia SK. Autophagy and apoptosis: where do they meet? Apoptosis. 2014;19(4):555–66.CrossRef
34.
go back to reference Cao Y, Luo Y, Zou J, Ouyang J, Cai Z, Zeng X, et al. Autophagy and its role in gastric cancer. Clin Chim Acta. 2019;489:10–20.CrossRef Cao Y, Luo Y, Zou J, Ouyang J, Cai Z, Zeng X, et al. Autophagy and its role in gastric cancer. Clin Chim Acta. 2019;489:10–20.CrossRef
35.
go back to reference Zhang H, Luo X, Ke J, Duan Y, He Y, Zhang D, et al. Procyanidins, from Castanea mollissima Bl. Shell, induces autophagy following apoptosis associated with PI3K/AKT/mTOR inhibition in HepG2 cells. Biomed Pharmacother. 2016;81:15–24.CrossRef Zhang H, Luo X, Ke J, Duan Y, He Y, Zhang D, et al. Procyanidins, from Castanea mollissima Bl. Shell, induces autophagy following apoptosis associated with PI3K/AKT/mTOR inhibition in HepG2 cells. Biomed Pharmacother. 2016;81:15–24.CrossRef
36.
go back to reference Zhang R, Yu Q, Lu W, Shen J, Zhou D, Wang Y, et al. Grape seed procyanidin B2 promotes the autophagy and apoptosis in colorectal cancer cells via regulating PI3K/Akt signaling pathway. Onco Targets Ther. 2019;12:4109–18.CrossRef Zhang R, Yu Q, Lu W, Shen J, Zhou D, Wang Y, et al. Grape seed procyanidin B2 promotes the autophagy and apoptosis in colorectal cancer cells via regulating PI3K/Akt signaling pathway. Onco Targets Ther. 2019;12:4109–18.CrossRef
37.
go back to reference Díaz P, Valenzuela Valderrama M, Bravo J, Quest AFG. Helicobacter pylori and gastric Cancer: adaptive cellular mechanisms involved in disease progression. Front Microbiol. 2018;9:5.CrossRef Díaz P, Valenzuela Valderrama M, Bravo J, Quest AFG. Helicobacter pylori and gastric Cancer: adaptive cellular mechanisms involved in disease progression. Front Microbiol. 2018;9:5.CrossRef
38.
go back to reference Singh SS, Yap WN, Arfuso F, Kar S, Wang C, Cai W, et al. Targeting the PI3K/Akt signaling pathway in gastric carcinoma: a reality for personalized medicine? World J Gastroenterol. 2015;21(43):12261–73.CrossRef Singh SS, Yap WN, Arfuso F, Kar S, Wang C, Cai W, et al. Targeting the PI3K/Akt signaling pathway in gastric carcinoma: a reality for personalized medicine? World J Gastroenterol. 2015;21(43):12261–73.CrossRef
39.
go back to reference Strozyk E, Kulms D. The role of AKT/mTOR pathway in stress response to UV-irradiation: implication in skin carcinogenesis by regulation of apoptosis, autophagy and senescence. Int J Mol Sci. 2013;14(8):15260–85.CrossRef Strozyk E, Kulms D. The role of AKT/mTOR pathway in stress response to UV-irradiation: implication in skin carcinogenesis by regulation of apoptosis, autophagy and senescence. Int J Mol Sci. 2013;14(8):15260–85.CrossRef
40.
go back to reference Feng J, Wang C, Liu T, Li J, Wu L, Yu Q, et al. Procyanidin B2 inhibits the activation of hepatic stellate cells and angiogenesis via the hedgehog pathway during liver fibrosis. J Cell Mol Med. 2019;23(9):6479–93.CrossRef Feng J, Wang C, Liu T, Li J, Wu L, Yu Q, et al. Procyanidin B2 inhibits the activation of hepatic stellate cells and angiogenesis via the hedgehog pathway during liver fibrosis. J Cell Mol Med. 2019;23(9):6479–93.CrossRef
Metadata
Title
Procyanidin B2 induces apoptosis and autophagy in gastric cancer cells by inhibiting Akt/mTOR signaling pathway
Authors
Yuqin Li
Xiaolan Lu
Peiying Tian
Kai Wang
Jianping Shi
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2021
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-021-03225-1

Other articles of this Issue 1/2021

BMC Complementary Medicine and Therapies 1/2021 Go to the issue