Cryptotanshinone inhibits cellular proliferation of human lung cancer cells through downregulation ofIGF-1R/PI3K/Akt signaling pathway

Zhang,Jingtao; Wen,Guilan; Sun,Longhua; Yuan,Wenxin; Wang,Ran; Zeng,Qinghua; Zhang,Guangyi; Yu,Bentong

doi:10.3892/or.2018.6638

Cryptotanshinone inhibits cellular proliferation of human lung cancer cells through downregulation ofIGF-1R/PI3K/Akt signaling pathway

Authors:
- Jingtao Zhang
- Guilan Wen
- Longhua Sun
- Wenxin Yuan
- Ran Wang
- Qinghua Zeng
- Guangyi Zhang
- Bentong Yu
View Affiliations

Affiliations: Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Respiratory, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Ultrasonography, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China, Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: August 10, 2018 https://doi.org/10.3892/or.2018.6638
Pages: 2926-2934

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

Lung cancer is one of the most commonly diagnosed malignancies worldwide. Cryptotanshinone (CPT) is a diterpene quinone compound extracted from natural plants and has been reported to have anticancer effects in several cancers including human lung cancer. However, the mechanism by which CPT acts to prevent lung cancer cell growth is largely unknown. In the present study, by using MTT assay, colony formation assay, wound healing and western blotting assays, the effects of CPT on the cell proliferation and migration of human lung cancer cells and the potential cellular signaling mechanisms were investigated. The data demonstrated that CPT exhibited anti-proliferative effects against A549 and H1299 cells. In parallel, the migration of A549 cells was also markedly inhibited by CPT treatment. Further study indicated that CPT not only inhibited the basal phosphorylation level of insulin-like growth factor 1 receptor (IGF-1R) and RAC-alpha serine/threonine-protein kinase (Akt), but also blocked IGF-1 induced IGF-1R and Akt phosphorylation. Finally, it was demonstrated that pretreatment with CPT inhibited IGF-1 induced cell proliferation of A549 and H1299 cells. In conclusion, the results of the present study indicated that CPT inhibits the proliferation and migration of lung cancer cells via a mechanism that involves inhibiting the IGF-1R-mediated phosphoinositide 3-kinase/Akt signaling pathway. The data provides evidence that CPT could be developed as a potential therapeutic agent for the treatment of lung cancer.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
2	Sakashita S, Sakashita M and Tsao Sound M: Genes and pathology of non-small cell lung carcinoma. Semin Oncol. 41:28–39. 2014. View Article : Google Scholar : PubMed/NCBI
3	Hu P, He J, Liu S, Wang M, Pan B and Zhang W: beta2-adrenergic receptor activation promotes the proliferation of A549 lung cancer cells via the ERK1/2/CREB pathway. Oncol Rep. 36:1757–1763. 2016. View Article : Google Scholar : PubMed/NCBI
4	Youlden DR, Cramb SM and Baade PD: The international epidemiology of lung cancer: Geographical distribution and secular trends. J Thorac Oncol. 3:819–831. 2008. View Article : Google Scholar : PubMed/NCBI
5	Efferth T, Li PC, Konkimalla VS and Kaina B: From traditional Chinese medicine to rational cancer therapy. Trends Mol Med. 13:353–361. 2007. View Article : Google Scholar : PubMed/NCBI
6	Tan W, Lu J, Huang M, Li Y, Chen M, Wu G, Gong J, Zhong Z, Xu Z, Dang Y, et al: Anticancer natural products isolated from chinese medicinal herbs. Chin Med. 6:272011. View Article : Google Scholar : PubMed/NCBI
7	Singla AK, Garg A and Aggarwal D: Paclitaxel and its formulations. Int J Pharm. 235:179–192. 2002. View Article : Google Scholar : PubMed/NCBI
8	Wu CY, Cherng JY, Yang YH, Lin CL, Kuan FC, Lin YY, Lin YS, Shu LH, Cheng YC, Liu HT, et al: Danshen improves survival of patients with advanced lung cancer and targeting the relationship between macrophages and lung cancer cells. Oncotarget. 8:90925–90947. 2017.PubMed/NCBI
9	Chen X, Guo J, Bao J, Lu J and Wang Y: The anticancer properties of Salvia miltiorrhiza Bunge (Danshen): A systematic review. Med Res Rev. 34:768–794. 2014. View Article : Google Scholar : PubMed/NCBI
10	Shin DS, Kim HN, Shin KD, Yoon YJ, Kim SJ, Han DC and Kwon BM: Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells. Cancer Res. 69:193–202. 2009. View Article : Google Scholar : PubMed/NCBI
11	Kim JH, Jeong SJ, Kwon TR, Yun SM, Jung JH, Kim M, Lee HJ, Lee MH, Ko SG, Chen CY, et al: Cryptotanshinone enhances TNF-alpha-induced apoptosis in chronic myeloid leukemia KBM-5 cells. Apoptosis. 16:696–707. 2011. View Article : Google Scholar : PubMed/NCBI
12	Lu L, Li C, Li D, Wang Y, Zhou C, Shao W, Peng J, You Y, Zhang X and Shen X: Cryptotanshinone inhibits human glioma cell proliferation by suppressing STAT3 signaling. Mol Cell Biochem. 381:273–282. 2013. View Article : Google Scholar : PubMed/NCBI
13	Park IJ, Yang WK, Nam SH, Hong J, Yang KR, Kim J, Kim SS, Choe W, Kang I and Ha J: Cryptotanshinone induces G1 cell cycle arrest and autophagic cell death by activating the AMP-activated protein kinase signal pathway in HepG2 hepatoma. Apoptosis. 19:615–628. 2014. View Article : Google Scholar : PubMed/NCBI
14	Ge Y, Yang B, Chen Z and Cheng R: Cryptotanshinone suppresses the proliferation and induces the apoptosis of pancreatic cancer cells via the STAT3 signaling pathway. Mol Med Rep. 12:7782–7788. 2015. View Article : Google Scholar : PubMed/NCBI
15	Li S, Wang H, Hong L, Liu W, Huang F, Wang J, Wang P, Zhang X and Zhou J: Cryptotanshinone inhibits breast cancer cell growth by suppressing estrogen receptor signaling. Cancer Biol Ther. 16:176–184. 2015. View Article : Google Scholar : PubMed/NCBI
16	Li W, Saud SM, Young MR, Colburn NH and Hua B: Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro. Mol Cell Biochem. 406:63–73. 2015. View Article : Google Scholar : PubMed/NCBI
17	Ye T, Zhu S, Zhu Y, Feng Q, He B, Xiong Y, Zhao L, Zhang Y, Yu L and Yang L: Cryptotanshinone induces melanoma cancer cells apoptosis via ROS-mitochondrial apoptotic pathway and impairs cell migration and invasion. Biomed Pharmacother. 82:319–326. 2016. View Article : Google Scholar : PubMed/NCBI
18	Werner H and Bruchim I: The insulin-like growth factor-I receptor as an oncogene. Arch Physiol Biochem. 115:58–71. 2009. View Article : Google Scholar : PubMed/NCBI
19	Resnik JL, Reichart DB, Huey K, Webster NJ and Seely BL: Elevated insulin-like growth factor I receptor autophosphorylation and kinase activity in human breast cancer. Cancer Res. 58:1159–1164. 1998.PubMed/NCBI
20	Weber MM, Fottner C, Liu SB, Jung MC, Engelhardt D and Baretton GB: Overexpression of the insulin-like growth factor I receptor in human colon carcinomas. Cancer. 95:2086–2095. 2002. View Article : Google Scholar : PubMed/NCBI
21	Sharon C, Baranwal S, Patel NJ, Rodriguez-Agudo D, Pandak WM, Majumdar AP, Krystal G and Patel BB: Inhibition of insulin-like growth factor receptor/AKT/mammalian target of rapamycin axis targets colorectal cancer stem cells by attenuating mevalonate-isoprenoid pathway in vitro and in vivo. Oncotarget. 6:15332–15347. 2015. View Article : Google Scholar : PubMed/NCBI
22	Teng JA, Wu SG, Chen JX, Li Q, Peng F, Zhu Z, Qin J and He ZY: The activation of ERK1/2 and JNK MAPK signaling by insulin/IGF-1 is responsible for the development of colon cancer with type 2 diabetes mellitus. PLoS One. 11:e01498222016. View Article : Google Scholar : PubMed/NCBI
23	Zhou Y, Zeng C, Li X, Wu PL, Yin L, Yu XL, Zhou YF and Xue Q: IGF-I stimulates ERbeta and aromatase expression via IGF1R/PI3K/AKT-mediated transcriptional activation in endometriosis. J Mol Med. 94:887–897. 2016. View Article : Google Scholar : PubMed/NCBI
24	Hennessy BT, Smith DL, Ram PT, Lu Y and Mills GB: Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov. 4:988–1004. 2005. View Article : Google Scholar : PubMed/NCBI
25	Kim WY, Jin Q, Oh SH, Kim ES, Yang YJ, Lee DH, Feng L, Behrens C, Prudkin L, Miller YE, et al: Elevated epithelial insulin-like growth factor expression is a risk factor for lung cancer development. Cancer Res. 69:7439–7448. 2009. View Article : Google Scholar : PubMed/NCBI
26	Kim WY, Prudkin L, Feng L, Kim ES, Hennessy B, Lee JS, Lee JJ, Glisson B, Lippman SM, Wistuba II, et al: Epidermal growth factor receptor and K-Ras mutations and resistance of lung cancer to insulin-like growth factor 1 receptor tyrosine kinase inhibitors. Cancer. 118:3993–4003. 2012. View Article : Google Scholar : PubMed/NCBI
27	Chen L, Wang HJ, Xie W, Yao Y, Zhang YS and Wang H: Cryptotanshinone inhibits lung tumorigenesis and induces apoptosis in cancer cells in vitro and in vivo. Mol Med Rep. 9:2447–2452. 2014. View Article : Google Scholar : PubMed/NCBI
28	Peled N, Wynes MW, Ikeda N, Ohira T, Yoshida K, Qian J, Ilouze M, Brenner R, Kato Y, Mascaux C, et al: Insulin-like growth factor-1 receptor (IGF-1R) as a biomarker for resistance to the tyrosine kinase inhibitor gefitinib in non-small cell lung cancer. Cell Oncol. 36:277–288. 2013. View Article : Google Scholar
29	Engelman JA: Targeting PI3K signalling in cancer: Opportunities, challenges and limitations. Nat Rev Cancer. 9:550–562. 2009. View Article : Google Scholar : PubMed/NCBI
30	Thorpe LM, Yuzugullu H and Zhao JJ: PI3K in cancer: Divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 15:7–24. 2015. View Article : Google Scholar : PubMed/NCBI
31	Sun CH, Chang YH and Pan CC: Activation of the PI3K/Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder. Histopathology. 58:1054–1063. 2011. View Article : Google Scholar : PubMed/NCBI
32	Luo J, Manning BD and Cantley LC: Targeting the PI3K-Akt pathway in human cancer: Rationale and promise. Cancer Cell. 4:257–262. 2003. View Article : Google Scholar : PubMed/NCBI
33	Kelly PN and Strasser A: The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapy. Cell Death Differ. 18:1414–1424. 2011. View Article : Google Scholar : PubMed/NCBI
34	LeRoith D and Roberts CT Jr: The insulin-like growth factor system and cancer. Cancer Lett. 195:127–137. 2003. View Article : Google Scholar : PubMed/NCBI
35	De Luca A, Maiello MR, D'Alessio A, Pergameno M and Normanno N: The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: Role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets. 16 Suppl 2:S17–S27. 2012. View Article : Google Scholar : PubMed/NCBI
36	Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y and Greenberg ME: Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 91:231–241. 1997. View Article : Google Scholar : PubMed/NCBI