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Inhibitory effect of oleanolic acid on hepatocellular carcinoma via ERK-p53-mediated cell cycle arrest and mitochondrial-dependent apoptosis.
Carcinogenesis. 2013 Jun; 34(6):1323-30.C

Abstract

Incidence of hepatocellular carcinoma (HCC) is dramatically increasing and is the third cause of cancer death worldwide. One key approach to control HCC is chemoprevention by naturally occurring agents. This study aims at investigating the antitumor effect of oleanolic acid (OA) and the molecular mechanisms. BALB/c mice were injected subcutaneously with HepG2 cells to establish transplanted tumors. Apoptosis and cell cycle arrest-related markers and signaling cascades were determined by western blot, immunofluorescence, reverse transcriptase-polymerase chain reaction and flow cytometric analysis. OA exhibited inhibitory effect on HCC through induction of apoptosis and cell cycle arrest both in transplanted tumors and in HepG2 cells. OA induced apoptosis through mitochondrial pathway, evidenced by inhibition of Akt/mammalian target of rapamycin pathway, mitochondrial dysfunction, transient increase of adenosine triphosphate, increase of Bax/Bcl-2 ratio, increased release of cytochrome c and activation of caspase/poly (ADP-ribose) polymerase. Activation of mitochondrial apoptotic pathway may be due to reactive oxygen species generated by mitochondrial fatty acid oxidation, resulted from enhancement of lipolysis regulated by cyclic adenosine 3',5'-monophosphate response element-binding protein-hormone-sensitive lipase/peroxisome proliferator-activated receptor γ signaling. OA induced G2/M cell cycle arrest through p21-mediated downregulation of cyclin B1/cdc2. Cyclooxygenase-2 (COX-2) and p53 were involved in OA-exerted effect, and extracellular signal-regulated kinase-p53 signaling played a central role in OA-activated cascades responsible for apoptosis and cell cycle arrest. OA demonstrated significant antitumor activities in HCC in vivo and in vitro models. These data provide new insights into the mechanisms underlying the antitumor effect of OA.

Authors+Show Affiliations

Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23404993

Citation

Wang, Xin, et al. "Inhibitory Effect of Oleanolic Acid On Hepatocellular Carcinoma Via ERK-p53-mediated Cell Cycle Arrest and Mitochondrial-dependent Apoptosis." Carcinogenesis, vol. 34, no. 6, 2013, pp. 1323-30.
Wang X, Bai H, Zhang X, et al. Inhibitory effect of oleanolic acid on hepatocellular carcinoma via ERK-p53-mediated cell cycle arrest and mitochondrial-dependent apoptosis. Carcinogenesis. 2013;34(6):1323-30.
Wang, X., Bai, H., Zhang, X., Liu, J., Cao, P., Liao, N., Zhang, W., Wang, Z., & Hai, C. (2013). Inhibitory effect of oleanolic acid on hepatocellular carcinoma via ERK-p53-mediated cell cycle arrest and mitochondrial-dependent apoptosis. Carcinogenesis, 34(6), 1323-30. https://doi.org/10.1093/carcin/bgt058
Wang X, et al. Inhibitory Effect of Oleanolic Acid On Hepatocellular Carcinoma Via ERK-p53-mediated Cell Cycle Arrest and Mitochondrial-dependent Apoptosis. Carcinogenesis. 2013;34(6):1323-30. PubMed PMID: 23404993.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibitory effect of oleanolic acid on hepatocellular carcinoma via ERK-p53-mediated cell cycle arrest and mitochondrial-dependent apoptosis. AU - Wang,Xin, AU - Bai,Hua, AU - Zhang,Xiaodi, AU - Liu,Jiangzheng, AU - Cao,Peipei, AU - Liao,Nai, AU - Zhang,Wei, AU - Wang,Zhao, AU - Hai,Chunxu, Y1 - 2013/02/12/ PY - 2013/2/14/entrez PY - 2013/2/14/pubmed PY - 2013/8/2/medline SP - 1323 EP - 30 JF - Carcinogenesis JO - Carcinogenesis VL - 34 IS - 6 N2 - Incidence of hepatocellular carcinoma (HCC) is dramatically increasing and is the third cause of cancer death worldwide. One key approach to control HCC is chemoprevention by naturally occurring agents. This study aims at investigating the antitumor effect of oleanolic acid (OA) and the molecular mechanisms. BALB/c mice were injected subcutaneously with HepG2 cells to establish transplanted tumors. Apoptosis and cell cycle arrest-related markers and signaling cascades were determined by western blot, immunofluorescence, reverse transcriptase-polymerase chain reaction and flow cytometric analysis. OA exhibited inhibitory effect on HCC through induction of apoptosis and cell cycle arrest both in transplanted tumors and in HepG2 cells. OA induced apoptosis through mitochondrial pathway, evidenced by inhibition of Akt/mammalian target of rapamycin pathway, mitochondrial dysfunction, transient increase of adenosine triphosphate, increase of Bax/Bcl-2 ratio, increased release of cytochrome c and activation of caspase/poly (ADP-ribose) polymerase. Activation of mitochondrial apoptotic pathway may be due to reactive oxygen species generated by mitochondrial fatty acid oxidation, resulted from enhancement of lipolysis regulated by cyclic adenosine 3',5'-monophosphate response element-binding protein-hormone-sensitive lipase/peroxisome proliferator-activated receptor γ signaling. OA induced G2/M cell cycle arrest through p21-mediated downregulation of cyclin B1/cdc2. Cyclooxygenase-2 (COX-2) and p53 were involved in OA-exerted effect, and extracellular signal-regulated kinase-p53 signaling played a central role in OA-activated cascades responsible for apoptosis and cell cycle arrest. OA demonstrated significant antitumor activities in HCC in vivo and in vitro models. These data provide new insights into the mechanisms underlying the antitumor effect of OA. SN - 1460-2180 UR - https://www.unboundmedicine.com/medline/citation/23404993/Inhibitory_effect_of_oleanolic_acid_on_hepatocellular_carcinoma_via_ERK_p53_mediated_cell_cycle_arrest_and_mitochondrial_dependent_apoptosis_ L2 - https://academic.oup.com/carcin/article-lookup/doi/10.1093/carcin/bgt058 DB - PRIME DP - Unbound Medicine ER -