Gambogic Acid Induces Cell Apoptosis and Inhibits MAPK Pathway in PTEN−/−/p53−/− Prostate Cancer Cells In Vitro and Ex Vivo

Hong Pan; Li-yuan Lu; Xue-qian Wang; Bin-xue Li; Kathleen Kelly; Hong-sheng Lin

doi:10.1007/s11655-017-2410-3

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Gambogic Acid Induces Cell Apoptosis and Inhibits MAPK Pathway in PTEN−/−/p53−/− Prostate Cancer Cells In Vitro and Ex Vivo

Updated：2021-08-27

- Gambogic Acid Induces Cell Apoptosis and Inhibits MAPK Pathway in PTEN−/−/p53−/− Prostate Cancer Cells In Vitro and Ex Vivo
- Chinese Journal of Integrative Medicine Vol. 24, Issue 2, Pages: 109-116(2018)
- Affiliations：
  
  1. Clinical Medical College, Beijing University of Chinese Medicine,Beijing,China
  2. Laboratory of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences,Beijing,China
  3. Laboratory of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda,USA
- Author bio：
- Funds：
  
  Supported by an International Science and Technology Cooperation Program (No. 2013DFA32540), China
- DOI：10.1007/s11655-017-2410-3
  CLC：
- Published：2018，
  
  Published Online：3 June 2017，
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Pan, H., Lu, Ly., Wang, Xq. et al. Gambogic Acid Induces Cell Apoptosis and Inhibits MAPK Pathway in PTEN−/−/p53−/− Prostate Cancer Cells In Vitro and Ex Vivo., Chin. J. Integr. Med. 24, 109–116 (2018). https://doi.org/10.1007/s11655-017-2410-3

Hong Pan, Li-yuan Lu, Xue-qian Wang, et al. Gambogic Acid Induces Cell Apoptosis and Inhibits MAPK Pathway in PTEN−/−/p53−/− Prostate Cancer Cells In Vitro and Ex Vivo. [J]. Chinese Journal of Integrative Medicine 24(2):109-116(2018)
Pan, H., Lu, Ly., Wang, Xq. et al. Gambogic Acid Induces Cell Apoptosis and Inhibits MAPK Pathway in PTEN−/−/p53−/− Prostate Cancer Cells In Vitro and Ex Vivo., Chin. J. Integr. Med. 24, 109–116 (2018). https://doi.org/10.1007/s11655-017-2410-3 DOI：

Hong Pan, Li-yuan Lu, Xue-qian Wang, et al. Gambogic Acid Induces Cell Apoptosis and Inhibits MAPK Pathway in PTEN−/−/p53−/− Prostate Cancer Cells In Vitro and Ex Vivo. [J]. Chinese Journal of Integrative Medicine 24(2):109-116(2018) DOI： 10.1007/s11655-017-2410-3.

摘要

To investigate the effect of gambogic acid (GA) on the growth and cell death of castrate resistant prostate cancer (PC) with phosphate and tension homology (PTEN) and p53 genes deleted in vitro and ex vivo

and elucidate the underlying possible molecular mechanisms. PTEN−/−/p53−/− PC cells and Los Angeles prostate cancer-4 (LAPC-4) cells were treated with GA for 24 h and 48 h

then cell viability was determined by cell proliferation assay. PTEN−/−/p53−/− PC cells organoids number was calculated under GA treatment for 1 week. In addition

cell titer glo assay was performed to analyze 3 dimensional cell viability of patients derived xenografts (PDX) 170.2 organoids. Flow cytometry was used to detect apoptotic cells treated with GA. And confocal image was performed to detect the apoptotic mitochondrial morphological changes. Apoptotic cell death related protein levels were measured through Western blot (WB) in GA treated cells and organoids. The expression levels of mitogen-activated protein kinases (MAPKs) pathway related ribonucleic acid (RNAs) and proteins were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and WB

respectively. The treatment of GA significantly reduced cell viability of PTEN−/−/p53−/− PC cells and LAPC-4 in a time- and concentration-dependent manner. In organoids

GA showed strong inhibition towards organoids’ numbers and diameters and continuously led to a complete organoids inhibition with GA 150 nmol/L. Ex vivo results validated that GA 1 μmol/L inhibited 44.6% PDX170.2 organoids growth. As for mechanism

flow cytometry detected continuously increased apoptotic portion under GA treatment from 1.98% to 11.78% (6 h) and 29.94% (8 h

P<0.05). In addition

mitochondrial fragmentation emerged in GA treated cells indicated the mitochondrial apoptotic pathway might be involved. Furthermore

WB detected caspases-3

-9 activation and light chain (LC)-3 conversion with GA treatment. WB revealed decreased activity of MAPK pathway and down-regulation of downstream c-fos oncogene RNA level was detected by RT-PCR before undergoing apoptosis (P<0.05). GA was a potent anti-tumor compound as for PTEN−/−/p53−/− PC

which contributed to cell apoptosis via inhibition of the MAPK pathway and c-fos.

Abstract

and elucidate the underlying possible molecular mechanisms. PTEN−/−/p53−/− PC cells and Los Angeles prostate cancer-4 (LAPC-4) cells were treated with GA for 24 h and 48 h

then cell viability was determined by cell proliferation assay. PTEN−/−/p53−/− PC cells organoids number was calculated under GA treatment for 1 week. In addition

respectively. The treatment of GA significantly reduced cell viability of PTEN−/−/p53−/− PC cells and LAPC-4 in a time- and concentration-dependent manner. In organoids

flow cytometry detected continuously increased apoptotic portion under GA treatment from 1.98% to 11.78% (6 h) and 29.94% (8 h

P<0.05). In addition

mitochondrial fragmentation emerged in GA treated cells indicated the mitochondrial apoptotic pathway might be involved. Furthermore

WB detected caspases-3

which contributed to cell apoptosis via inhibition of the MAPK pathway and c-fos.

关键词

gambogic acidprostate cancerapoptosismitogen-activated protein kinasePTEN−/−/p53−/−

Keywords

gambogic acidprostate cancerapoptosismitogen-activated protein kinasePTEN−/−/p53−/−

references

Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA 2014;64:9–29.

Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893–2917.

Chen R, Ren S, Yiu MK, Fai NC, Cheng WS, Ian LH, et al. Prostate cancer in Asia: a collaborative report. Asian J Urol 2014;1:15–27.

Yang X, Monn MF, Liu L, Liu Y, Su J, Lyu T, et al. Incidental prostate cancer in Asian men: high prevalence of incidental prostatic adenocarcinoma in Chinese patients undergoing radical cystoprostatect-omy for treatment of bladder cancer and selection of candidates for prostate-sparing cystectomy. Prostate 2015;75:845–854.

Roudier MP, True LD, Higano CS, Vesselle H, Ellis W, Lange P, et al. Phenotypic heterogeneity of end-stage prostate carcinoma metastatic to bone. Hum Pathol 2003;34:646–653.

Sircar K, Yoshimoto M, Monzon FA, Koumakpayi IH, Katz RL, Khanna A, et al. PTEN genomic deletion is associated with p-Akt and AR signalling in poorer outcome, hormone refractory prostate cancer. J Pathol 2009;218:505–513.

Schlomm T, Iwers L, Kirstein P, Jessen B, Kollermann J, Prien K, et al. Clinical significance of p53 alterations in surgically treated prostate cancers. Mod Pathol 2008;21:1371–1378.

Agell L, Hernandez S, de Muga S, Lorente JA, Juanpere N, Esgueva R, et al. KLF6 and TP53 mutations are a rare event in prostate cancer: distinguishing between Taq polymerase artifacts and true mutations. Mod Pathol 2008;21:1470–1478.

Marquez F, Babio N, Bullo M, Salas-Salvado J. Evaluation of the safety and efficacy of hydroxycitric acid or Garcinia cambogia extracts in humans. Crit Rev Food Sci Nutr 2012;52:585–594.

Panthong A, Norkaew P, Kanjanapothi D, Taesotikul T, Anantachoke N, Reutrakul V. Anti-inflammatory, analgesic and antipyretic activities of the extract of gamboge from Garcinia hanburyi Hook f. J Ethnopharmacol 2007;111:335–340.

Zhang HZ, Kasibhatla S, Wang Y, Herich J, Guastella J, Tseng B, et al. Discovery, characterization and SAR of gambogic acid as a potent apoptosis inducer by a HTS assay. Bioorg Med Chem 2004;12:309–317.

Wu ZQ, Guo QL, You QD, Zhao L, Gu HY. Gambogic acid inhibits proliferation of human lung carcinoma SPC-A1 cells in vivo and in vitro and represses telomerase activity and telomerase reverse transcriptase mRNA expression in the cells. Biol Pharm Bull 2004;27:1769–1774.

Gu H, Rao S, Zhao J, Wang J, Mu R, Rong J, et al. Gambogic acid reduced bcl-2 expression via p53 in human breast MCF-7 cancer cells. J Cancer Res Clin Oncol 2009;135:1777–1782.

Lü L, Tang D, Wang L, Huang LQ, Jiang GS, Xiao XY, et al. Gambogic acid inhibits TNF-a induced invasion of human prostate cancer PC3 cells in vitro through PI3K/ Akt and NF-?B signaling pathways. Acta Pharmacol Sin 2012;33:531–541.

Prasad S, Pandey MK, Yadav VR, Aggarwal BB. Gambogic acid inhibits STAT3 phosphorylation through activation of protein tyrosine phosphatase SHP-1: potential role in proliferation and apoptosis. Cancer Prev Res (Phila) 2011;4:1084–1094.

Abou-Kheir WG, Hynes PG, Martin PL, Pierce R, Kelly K. Characterizing the contribution of stem/progenitor cells to tumorigenesis in the PTEN-/-TP53-/- prostate cancer model. Stem Cells 2010;28:2129–2140.

Karthaus WR, Iaquinta PJ, Drost J, Gracanin A, van Boxtel R, Wongvipat J, et al. Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell 2014;159:163–175.

Liu YN, Abou-Kheir W, Yin JJ, Fang L, Hynes P, Casey O, et al. Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor beta-initiated prostate cancer epithelial-mesenchymal transition. Mol Cell Biol 2012;32:941–953.

Agarwal S, Hynes PG, Tillman HS, Lake R, Abou-Kheir WG, Fang L, et al. Identification of different classes of luminal progenitor cells within prostate tumors. Cell Rep 2015;13:2147–2158.

Lee YR, Lei HY, Liu MT, Wang JR, Chen SH, Jiang-Shieh YF, et al. Autophagic machinery activated by dengue virus enhances virus replication. Virology 2008;374:240–248.

Zhang HZ, Kasibhatla S, Wang Y, Herich J, Guastella J, Tseng B, et al. Characterization and SAR of gambogic acid as a potent apoptosis inducer by a HTS assay. Bioorg Med Chem 2004;12:309–317.

Chi Y, Zhan XK, Yu H, Xie GR, Wang ZZ, Xiao W, et al. An open-labeled, randomized, multicenter phase a study of gambogic acid injection for advanced malignant tumors. Chin Med J 2013;126:1642–1646.

Ning R, Wang XP, Zhan YR, Qi Q, Huang XF, Hu G, et al. Gambogic acid potentiates clopidogrel-induced apoptosis and attenuates irinotecan-induced apoptosis through downregulating human carboxylesterase 1 and-2. Xenobiotica 2016;46:816–824.

Jang JH, Kim JY, Sung EG, Kim EA, Lee TJ. Gambogic acid induces apoptosis and sensitizes TRAIL-mediated apoptosis through downregulation of cFLIPL in renal carcinoma Caki cells. Int J Oncol 2016;48:376–384.

Thida M, Kim DW, Tran TT, Pham MQ, Lee H, Kim I, et al. Gambogic acid induces apoptotic cell death in T98G glioma cells. Bioorg Med Chem Lett 2016;26:1097–1101.

Phillips R. Innovation: organoids-a better model for PC. Nat Rev Urol 2014,11:604.

Choi SY, Lin D, Gout PW, Collins CC, Xu Y, Wang Y. Lessons from patient-derived xenografts for better in vitro modeling of human cancer. Adv Drug Deliv Rev 2014;79:222–237.

Lawrence MG, Taylor RA, Toivanen R, Pedersen J, Norden S, Pook DW, et al. A preclinical xenograft model of PC using human tumors. Nat Protoc 2013;8:836–848.

Ritch CR, Cookson MS. Advances in the management of castration resistant PC. BMJ 2016;17:355.

Long JS, Ryan KM. New frontiers in promoting tumour cell death: targeting apoptosis, necroptosis and autophagy. Oncogene 2012;31:5045–5060.

Wang Y, Chen Y, Chen Z, Ke WJ, Qi LW, He J. Mechanism of gambogic acid-induced apoptosis in Raji cells. J Exp Hematol (Chin) 2009;17:88–91.

Zhong N, Jiang D, Zheng SY. Anticancer effect of gambogic acid in gastric cancer line SGC-7901. 2010 4th International Conference Bio-information Biomedicine Engineer IEEE, Genoa, Italy; 2010:1–6.

Nie F, Zhang X, Qi Q, Yang L, Yang Y, Liu W, et al. Reactive oxygen species accumulation contributes to gambogic acid induced apoptosis in human hepatoma SMMC-7721 cells. Toxicology 2009;260:60–67.

Li C, Qi Q, Lu N, Dai Q, Li F, Wang X, et al. Gambogic acid promotes apoptosis and resistance to metastatic potential inMDAMB-231 human breast carcinoma cells. Biochem Cell Bio 2012;90:718–730.

Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG, Catez F, et al. The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 2001;1:515–525.

Karbowski M, Lee YJ, Gaume B, Jeong SY, Frank S, Nechushtan A, et al. Spatial and temporal association of Bax with mitochondrial fission sites, Drp1, and Mfn2 during apoptosis. J Cell Biol 2002;159:931–938.

Lewis TS, Shapiro PS, Ahn NG, Adv. Signal transduction through MAP kinase cascades. Adv Cancer Res 1998;74:49–139.

Feng Z, Joos HJ, Vallan C, Mühlbauer R, Altermatt HJ, Jaggi R. Apoptosis during castration-induced regression of the prostate is Fos dependent. Oncogene 1998;17:2593–2600.

Zhang X, Zhang L, Yang H, Huang X, Libermann TA, DeWolf WC, et al. c-Fos as a proapoptotic agent in TRAIL-induced apoptosis in PC cells. Cancer Res 2007;67:9425–9434.

Rebecca G, Nikki M, Simon J. ERK1/2, but not ERK5, is necessary and sufficient for phosphorylation and activation of c-Fos. Cellular Signalling 2009;21:969–977.

Shankar E, Song K, Corum SL, Bane KL, Wang H, Kao HY, et al. A signaling network controlling androgenic repression of c-Fos protein in prostate adenocarcinoma cells. J Biol Chem 2016;291:5512–5526.

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