A novel AKT inhibitor, AZD5363, inhibits phosphorylation of AKT downstream molecules, and activates phosphorylation of mTOR and SMG‑1 dependent on the liver cancer cell type

Zhang,Yuncheng; Zheng,Yuanwen; Faheem,Ali; Sun,Tiantong; Li,Chunyou; Li,Zhe; Zhao,Diantang; Wu,Chao; Liu,Jun

doi:10.3892/ol.2016.4111

A novel AKT inhibitor, AZD5363, inhibits phosphorylation of AKT downstream molecules, and activates phosphorylation of mTOR and SMG‑1 dependent on the liver cancer cell type

Authors:
- Yuncheng Zhang
- Yuanwen Zheng
- Ali Faheem
- Tiantong Sun
- Chunyou Li
- Zhe Li
- Diantang Zhao
- Chao Wu
- Jun Liu
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Affiliations: Department of Hepatobiliary Surgery and Center of Organ Transplantation, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China, Shandong University School of Medicine, Jinan, Shandong 250021, P.R. China
Published online on: January 14, 2016 https://doi.org/10.3892/ol.2016.4111
Pages: 1685-1692
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Due to frequent phosphoinositide 3‑kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway dysregulation, AKT is typically accepted as a promising anticancer therapeutic target. mTOR, in particular, represents a suitable therapeutic target for hepatocellular carcinoma, whilst suppressor with morphogenetic effect on genitalia family member‑1 (SMG‑1) is believed to serve a potential tumor suppressor role in human cancer. Despite SMG‑1 and mTOR belonging to the same PI3K‑related kinase family, the interactions between them are not yet fully understood. In the present study, a novel pyrrolopyrimidine‑derived compound, AZD5363, was observed to suppress proliferation in liver cancer Hep‑G2 and Huh‑7 cells by inhibiting the phosphorylation of downstream molecules in the AKT signal pathway, in a dose‑ and time‑dependent manner. AZD5363 activated the phosphorylation of mTOR, dependent on the liver cancer cell type, as it may have differing effects in various liver cancer cell lines. Additionally, AZD5363 also activated SMG‑1 within the same liver cancer cells types, which subsequently activated the phosphorylation of mTOR. In conclusion, the present study indicates that AZD5363 inhibited phosphorylation of AKT downstream molecules, and activated phosphorylation of mTOR and SMG‑1, dependent on the liver cancer type.

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1	Bruix J and Sherman M: American Association for the Study of Liver Diseases: Management of hepatocellular carcinoma: An update. Hepatology. 53:1020–1022. 2011. View Article : Google Scholar : PubMed/NCBI
2	El-Serag HB: Hepatocellular carcinoma. N Engl J Med. 365:1118–1127. 2011. View Article : Google Scholar : PubMed/NCBI
3	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
4	Bruix J and Sherman M: American Association for the Study of Liver Diseases: Management of hepatocellular carcinoma: An update. Hepatology. 53:1020–1022. 2011. View Article : Google Scholar : PubMed/NCBI
5	Abou-Alfa GK, Schwartz L, Ricci S, Amadori D, Santoro A, Figer A, De Greve J, Douillard JY, Lathia C, Schwartz B, et al: Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 24:4293–4300. 2006. View Article : Google Scholar : PubMed/NCBI
6	Mitsui H, Takuwa N, Maruyama T, Maekawa H, Hirayama M, Sawatari T, Hashimoto N, Takuwa Y and Kimura S: The MEK1-ERK map kinase pathway and the PI 3-kinase-Akt pathway independently mediate anti-apoptotic signals in HepG2 liver cancer cells. Int J Cancer. 92:55–62. 2001. View Article : Google Scholar : PubMed/NCBI
7	Bhaskar PT and Hay N: The two TORCs and Akt. Dev Cell. 12:487–502. 2007. View Article : Google Scholar : PubMed/NCBI
8	Engelman JA: Targeting PI3K signalling in cancer: Opportunities, challenges and limitations. Nat Rev Cancer. 9:550–562. 2009. View Article : Google Scholar : PubMed/NCBI
9	Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, Tovar V, Roayaie S, Minguez B, Sole M, et al: Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology. 135:1972–1983, 1983.e1-1983.e11. 2008. View Article : Google Scholar : PubMed/NCBI
10	Calvisi DF, Wang C, Ho C, et al: Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology. 140:1071–1083. 2011. View Article : Google Scholar : PubMed/NCBI
11	Stiles B, Wang Y, Stahl A, et al: Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected]. Proc Natl Acad Sci USA. 101:2082–2087. 2004. View Article : Google Scholar : PubMed/NCBI
12	O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, et al: mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66:1500–1508. 2006. View Article : Google Scholar : PubMed/NCBI
13	González-Estévez C, Felix DA, Smith MD, Paps J, Morley SJ, James V, Sharp TV and Aboobaker AA: SMG-1 and mTORC1 act antagonistically to regulate response to injury and growth in planarians. PLoS Genet. 8:e10026192012. View Article : Google Scholar : PubMed/NCBI
14	Han EK, Leverson JD, McGonigal T, Shah OJ, Woods KW, Hunter T, Giranda VL and Luo Y: Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition. Oncogene. 26:5655–5661. 2007. View Article : Google Scholar : PubMed/NCBI
15	Levy DS, Kahana JA and Kumar R: AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines. Blood. 113:1723–1729. 2009. View Article : Google Scholar : PubMed/NCBI
16	Lin J, Sampath D, Nannini MA, Lee BB, Degtyarev M, Oeh J, Savage H, Guan Z, Hong R, Kassees R, et al: Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res. 19:1760–1772. 2013. View Article : Google Scholar : PubMed/NCBI
17	Li Z, Oh DY, Nakamura K and Thiele CJ: Perifosine-induced inhibition of Akt attenuates brain-derived neurotrophic factor/TrkB-induced chemoresistance in neuroblastoma in vivo. Cancer. 117:5412–5422. 2011. View Article : Google Scholar : PubMed/NCBI
18	Liu R, Liu D, Trink E, Bojdani E, Ning G and Xing M: The Akt-specific inhibitor MK2206 selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathway. J Clin Endocrinol Metab. 96:E577–E585. 2011. View Article : Google Scholar : PubMed/NCBI
19	Davies BR, Greenwood H, Dudley P, Crafter C, Yu DH, Zhang J, Li J, Gao B, Ji Q, Maynard J, et al: Preclinical pharmacology of AZD5363, an inhibitor of AKT: Pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol Cancer Ther. 11:873–887. 2012. View Article : Google Scholar : PubMed/NCBI
20	Chong ZZ, Shang YC, Zhang L, Wang S and Maiese K: Mammalian target of rapamycin: Hitting the bull's-eye for neurological disorders. Oxid Med Cell Longev. 3:374–391. 2010. View Article : Google Scholar : PubMed/NCBI
21	Chong ZZ and Maiese K: Mammalian target of rapamycin signaling in diabetic cardiovascular disease. Cardiovasc Diabetol. 11:452012. View Article : Google Scholar : PubMed/NCBI
22	Yamashita A, Ohnishi T, Kashima I, Taya Y and Ohno S: Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay. Genes Dev. 15:2215–2228. 2001. View Article : Google Scholar : PubMed/NCBI
23	Grimson A, O'Connor S, Newman CL and Anderson P: SMG-1 is a phosphatidylinositol kinase-related protein kinase required for nonsense-mediated mRNA decay in Caenorhabditis elegans. Mol Cell Biol. 24:7483–7490. 2004. View Article : Google Scholar : PubMed/NCBI
24	Hwang J and Maquat LE: Nonsense-mediated mRNA decay (NMD) in animal embryogenesis: To die or not to die, that is the question. Curr Opin Genet Dev. 21:422–430. 2011. View Article : Google Scholar : PubMed/NCBI
25	Yamashita A: Role of SMG-1-mediated Upf1 phosphorylation in mammalian nonsense-mediated mRNA decay. Genes Cells. 18:161–175. 2013. View Article : Google Scholar : PubMed/NCBI
26	Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y, et al: Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med. 14:1351–1356. 2008. View Article : Google Scholar : PubMed/NCBI
27	Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V, Majumder PK, Baselga J and Rosen N: AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell. 19:58–71. 2011. View Article : Google Scholar : PubMed/NCBI
28	Karbowniczek M, Robertson GP and Henske EP: Rheb inhibits C-raf activity and B-raf/C-raf heterodimerization. J Biol Chem. 281:25447–25456. 2006. View Article : Google Scholar : PubMed/NCBI
29	Barrett D, Brown VI, Grupp SA and Teachey DT: Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies. Paediatr Drugs. 14:299–316. 2012. View Article : Google Scholar : PubMed/NCBI
30	Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, Botero ML, Llonch E, Atzori F, Di Cosimo S, et al: NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 68:8022–8030. 2008. View Article : Google Scholar : PubMed/NCBI
31	Yu K, Shi C, Toral-Barza L, Lucas J, Shor B, Kim JE, Zhang WG, Mahoney R, Gaydos C, Tardio L, et al: Beyond rapalog therapy: Preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res. 70:621–631. 2010. View Article : Google Scholar : PubMed/NCBI
32	Lloyd JP and Davies B: SMG1 is an ancient nonsense-mediated mRNA decay effector. Plant J. 76:800–810. 2013. View Article : Google Scholar : PubMed/NCBI
33	Oliveira V, Romanow WJ, Geisen C, Otterness DM, Mercurio F, Wang HG, Dalton WS and Abraham RT: A protective role for the human SMG-1 kinase against tumor necrosis factor-alpha-induced apoptosis. J Biol Chem. 283:13174–13184. 2008. View Article : Google Scholar : PubMed/NCBI
34	Nicholson P, Yepiskoposyan H, Metze S, Orozco Zamudio R, Kleinschmidt N and Mühlemann O: Nonsense-mediated mRNA decay in human cells: Mechanistic insights, functions beyond quality control and the double-life of NMD factors. Cell Mol Life Sci. 67:677–700. 2010. View Article : Google Scholar : PubMed/NCBI
35	Masse I, Molin L, Mouchiroud L, Vanhems P, Palladino F, Billaud M and Solari F: A novel role for the SMG-1 kinase in lifespan and oxidative stress resistance in Caenorhabditis elegans. PLoS One. 3:e33542008. View Article : Google Scholar : PubMed/NCBI
36	McIlwain DR, Pan Q, Reilly PT, Elia AJ, McCracken S, Wakeham AC, Itie-Youten A, Blencowe BJ and Mak TW: Smg1 is required for embryogenesis and regulates diverse genes via alternative splicing coupled to nonsense-mediated mRNA decay. Proc Natl Acad Sci USA. 107:12186–12191. 2010. View Article : Google Scholar : PubMed/NCBI
37	Gewandter JS, Bambara RA and O'Reilly MA: The RNA surveillance protein SMG1 activates p53 in response to DNA double-strand breaks but not exogenously oxidized mRNA. Cell Cycle. 10:2561–2567. 2011. View Article : Google Scholar : PubMed/NCBI
38	Gubanova E, Brown B, Ivanov SV, Helleday T, Mills GB, Yarbrough WG and Issaeva N: Downregulation of SMG-1 in HPV-positive head and neck squamous cell carcinoma due to promoter hypermethylation correlates with improved survival. Clin Cancer Res. 18:1257–1267. 2012. View Article : Google Scholar : PubMed/NCBI
39	Roberts TL, Ho U, Luff J, Lee CS, Apte SH, MacDonald KP, Raggat LJ, Pettit AR, Morrow CA, Waters MJ, et al: Smg1 haploinsufficiency predisposes to tumor formation and inflammation. Proc Natl Acad Sci USA. 110:E285–E294. 2013. View Article : Google Scholar : PubMed/NCBI
40	Altman JK, Sassano A and Platanias LC: Targeting mTOR for the treatment of AML. New agents and new directions. Oncotarget. 2:510–517. 2011. View Article : Google Scholar : PubMed/NCBI
41	Oviedo NJ, Pearson BJ, Levin M and Sánchez Alvarado A: Planarian PTEN homologs regulate stem cells and regeneration through TOR signaling. Dis Model Mech. 1:131–143. 2008. View Article : Google Scholar : PubMed/NCBI
42	Pearson BJ and Sánchez Alvarado A: A planarian p53 homolog regulates proliferation and self-renewal in adult stem cell lineages. Development. 137:213–221. 2010. View Article : Google Scholar : PubMed/NCBI