Casticin suppresses the carcinogenesis of small cell lung cancer H446 cells through activation of AMPK/FoxO3a signaling

Gong,Qian; Cao,Xiaozheng; Cao,Jianguo; Yang,Xiaohong; Zeng,Wenbin

doi:10.3892/or.2018.6547

Casticin suppresses the carcinogenesis of small cell lung cancer H446 cells through activation of AMPK/FoxO3a signaling

Authors:
- Qian Gong
- Xiaozheng Cao
- Jianguo Cao
- Xiaohong Yang
- Wenbin Zeng
View Affiliations

Affiliations: Pharmacy Department, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China, School of Pharmaceutical Sciences, and Molecular Imaging Research Center, Central South University, Changsha, Hunan 410013, P.R. China, Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China, Department of Pharmaceutical Science, Medical College, Hunan Normal University, Changsha, Hunan 410013, P.R. China, School of Pharmaceutical Sciences, and Molecular Imaging Research Center, Central South University, Changsha, Hunan 410013, P.R. China
Published online on: July 5, 2018 https://doi.org/10.3892/or.2018.6547
Pages: 1401-1410

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Casticin, a natural polymethoxyflavone isolated from A. annua, V. trifolia, and V. agnus‑castus induces apoptosis in cancer cells by activating FoxO3a. However, whether casticin inhibits in vitro carcinogenesis and cancer stem cell (CSC) characteristics, and whether casticin activates FoxO3a in small cell lung cancer (SCLC) cells remain unclear. We here demonstrated that casticin decreased sphere‑ and colony‑formation capabilities, and downregulated uPAR and CD133 in second‑generation spheres, which were considered as lung cancer stem‑like cells (LCSLCs), from SCLC H446 cells, in a concentration‑dependent manner. In addition, casticin dose‑dependently elevated the phosphorylation levels of AMPK and ACC, and reduced p‑FoxO3a expression. The above effects were attenuated by AMPK knockdown with small interfering RNAs (siRNAs). FoxO3a silencing resulted in decreased protein expression of FoxO3a, increased in vitro carcinogenesis and CSC characteristics, with no appreciable effects on AMPK and ACC phosphorylation, and displayed similar activities to those neutralizing the effects of casticin on in vitro carcinogenesis and CSC characteristics. These findings reveal a novel mechanism for regulating AMPK/FoxO3a signaling in response to casticin, suggesting a new strategy for SCLC therapy by targeting cancer stem‑like cells.

View Figures

View References

1	DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, Alteri R, Robbins AS and Jemal A: Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 64:252–271. 2014. View Article : Google Scholar : PubMed/NCBI
2	Zakaria N, Satar NA, Abu Halim NH, Ngalim SH, Yusoff NM, Lin J and Yahaya BH: Targeting lung cancer stem cells: Research and clinical impacts. Front Oncol. 7:802017. View Article : Google Scholar : PubMed/NCBI
3	Zhang Z, Zhou Y, Qian H, Shao G, Lu X, Chen Q, Sun X, Chen D, Yin R, Zhu H, et al: Stemness and inducing differentiation of small cell lung cancer NCI-H446 cells. Cell Death Dis. 4:e6332013. View Article : Google Scholar : PubMed/NCBI
4	Rahman M, Deleyrolle L, Vedam-Mai V, Azari H, Abd-El-Barr M and Reynolds BA: The cancer stem cell hypothesis: Failures and pitfalls. Neurosurgery. 68:531–545. 2011. View Article : Google Scholar : PubMed/NCBI
5	Tysnes BB and Bjerkvig R: Cancer initiation and progression: Involvement of stem cells and the microenvironment. Biochim Biophys Acta. 1775:283–297. 2007.PubMed/NCBI
6	Qiu X, Wang Z, Li Y, Miao Y, Ren Y and Luan Y: Characterization of sphere-forming cells with stem-like properties from the small cell lung cancer cell line H446. Cancer Lett. 323:161–170. 2012. View Article : Google Scholar : PubMed/NCBI
7	Xiao J, Mu JS, Liu TR and Xu HN: Dig the root of cancer: Targeting cancer stem cells therapy. J Med Discov. 2:1–6. 2017.
8	Sato A, Sunayama J, Okada M, Watanabe E, Seino S, Shibuya K, Suzuki K, Narita Y, Shibui S, Kayama T, et al: Glioma-initiating cell elimination by metformin activation of FOXO3 via AMPK. Stem Cells Transl Med. 1:811–824. 2012. View Article : Google Scholar : PubMed/NCBI
9	Yung MM, Chan DW, Liu VW, Yao KM and Ngan HY: Activation of AMPK inhibits cervical cancer cell growth through AKT/FOXO3a/FOXM1 signaling cascade. BMC Cancer. 13:3272013. View Article : Google Scholar : PubMed/NCBI
10	Queiroz EA, Puukila S, Eichler R, Sampaio SC, Forsyth HL, Lees SJ, Barbosa AM, Dekker RF, Fortes ZB and Khaper N: Metformin induces apoptosis and cell cycle arrest mediated by oxidative stress, AMPK and FOXO3a in MCF-7 breast cancer cells. PLoS One. 9:e982072014. View Article : Google Scholar : PubMed/NCBI
11	He L, Yang X, Cao X, Liu F, Quan M and Cao J: Casticin induces growth suppression and cell cycle arrest through activation of FOXO3a in hepatocellular carcinoma. Oncol Rep. 29:103–108. 2013. View Article : Google Scholar : PubMed/NCBI
12	Liu LP, Cao XC, Liu F, Quan MF, Sheng XF and Ren KQ: Casticin induces breast cancer cell apoptosis by inhibiting the expression of forkhead box protein M1. Oncol Lett. 7:1711–1717. 2014. View Article : Google Scholar : PubMed/NCBI
13	Jiang L, Cao XC, Cao JG, Liu F, Quan MF, Sheng XF and Ren KQ: Casticin induces ovarian cancer cell apoptosis by repressing FoxM1 through the activation of FOXO3a. Oncol Lett. 5:1605–1610. 2013. View Article : Google Scholar : PubMed/NCBI
14	Shrestha A, Nepal S, Kim MJ, Chang JH, Kim SH, Jeong GS, Jeong CH, Park GH, Jung S, Lim J, et al: Critical role of AMPK/FoxO3A axis in globular adiponectin-induced cell cycle arrest and apoptosis in cancer cells. J Cell Physiol. 231:357–369. 2016. View Article : Google Scholar : PubMed/NCBI
15	Zhao Y, Sun Y, Ding Y, Wang X, Zhou Y, Li W, Huang S, Li Z, Kong L, Guo Q, et al: GL-V9, a new synthetic flavonoid derivative, ameliorates DSS-induced colitis against oxidative stress by up-regulating Trx-1 expression via activation of AMPK/FOXO3a pathway. Oncotarget. 6:26291–26307. 2015. View Article : Google Scholar : PubMed/NCBI
16	Zheng F, Wu J, Zhao S, Luo Q, Tang Q, Yang L, Li L, Wu W and Hann SS: Baicalein increases the expression and reciprocal interplay of RUNX3 and FOXO3a through crosstalk of AMPKalpha and MEK/ERK1/2 signaling pathways in human non-small cell lung cancer cells. J Exp Clin Cancer Res. 34:412015. View Article : Google Scholar : PubMed/NCBI
17	Liu F, Cao X, Liu Z, Guo H, Ren K, Quan M, Zhou Y, Xiang H and Cao J: Casticin suppresses self-renewal and invasion of lung cancer stem-like cells from A549 cells through down-regulation of pAkt. Acta Biochim Biophys Sin. 46:15–21. 2014. View Article : Google Scholar : PubMed/NCBI
18	Bonini MG and Gantner BN: The multifaceted activities of AMPK in tumor progression-why the ‘one size fits all’ definition does not fit at all? IUBMB Life. 65:889–896. 2013. View Article : Google Scholar : PubMed/NCBI
19	Chen D, Cao J, Tian L, Liu F and Sheng X: Induction of apoptosis by casticin in cervical cancer cells through reactive oxygen species-mediated mitochondrial signaling pathways. Oncol Rep. 26:1287–1294. 2011.PubMed/NCBI
20	Zhou Y, Peng Y, Mao QQ, Li X, Chen MW, Su J, Tian L, Mao NQ, Long LZ, Quan MF, et al: Casticin induces caspase-mediated apoptosis via activation of mitochondrial pathway and upregulation of DR5 in human lung cancer cells. Asian Pac J Trop Med. 6:372–378. 2013. View Article : Google Scholar : PubMed/NCBI
21	Myatt SS and Lam EW: The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer. 7:847–859. 2007. View Article : Google Scholar : PubMed/NCBI
22	He M, Cao XC, He GC, Sheng XF, Ai XH and Wu YH: Casticin inhibits epithelial-mesenchymal transition of liver cancer stem cells of the SMMC-7721 cell line through downregulating Twist. Oncol Lett. 7:1625–1631. 2014. View Article : Google Scholar : PubMed/NCBI
23	He G, Cao X, He M, Sheng X, Wu Y and Ai X: Casticin inhibits self-renewal of liver cancer stem cells from the MHCC97 cell line. Oncol Lett. 7:2023–2028. 2014. View Article : Google Scholar : PubMed/NCBI
24	Chou CC, Lee KH, Lai IL, Wang D, Mo X, Kulp SK, Shapiro CL and Chen CS: AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Res. 74:4783–4795. 2014. View Article : Google Scholar : PubMed/NCBI
25	Guo Q, Liu Z, Jiang L, Liu M, Ma J, Yang C, Han L, Nan K and Liang X: Metformin inhibits growth of human non-small cell lung cancer cells via liver kinase B-1-independent activation of adenosine monophosphate-activated protein kinase. Mol Med Rep. 13:2590–2596. 2016. View Article : Google Scholar : PubMed/NCBI
26	Gutova M, Najbauer J, Gevorgyan A, Metz MZ, Weng Y, Shih CC and Aboody KS: Identification of uPAR-positive chemoresistant cells in small cell lung cancer. PLoS One. 2:e2432007. View Article : Google Scholar : PubMed/NCBI
27	LeBeau AM, Duriseti S, Murphy ST, Pepin F, Hann B, Gray JW, VanBrocklin HF and Craik CS: Targeting uPAR with antagonistic recombinant human antibodies in aggressive breast cancer. Cancer Res. 73:2070–2081. 2013. View Article : Google Scholar : PubMed/NCBI
28	Ma YY and Tao HQ: Role of urokinase plasminogen activator receptor in gastric cancer: A potential therapeutic target. Cancer Biother Radiopharm. 27:285–290. 2012. View Article : Google Scholar : PubMed/NCBI
29	Codony-Servat J, Verlicchi A and Rosell R: Cancer stem cells in small cell lung cancer. Transl Lung Cancer Res. 5:16–25. 2016.PubMed/NCBI
30	Chiacchiera F, Matrone A, Ferrari E, Ingravallo G, Lo Sasso G, Murzilli S, Petruzzelli M, Salvatore L, Moschetta A and Simone C: p38alpha blockade inhibits colorectal cancer growth in vivo by inducing a switch from HIF1alpha- to FoxO-dependent transcription. Cell Death Differ. 16:1203–1214. 2009. View Article : Google Scholar : PubMed/NCBI
31	Gopinath S, Malla RR, Gondi CS, Alapati K, Fassett D, Klopfenstein JD, Dinh DH, Gujrati M and Rao JS: Co-depletion of cathepsin B and uPAR induces G0/G1 arrest in glioma via FOXO3a mediated p27 upregulation. PLoS One. 5:e116682010. View Article : Google Scholar : PubMed/NCBI