| ORIGINAL ARTICLES |
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β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K |
| Shiyun Nie, Lizhong Chang, Ying Huang, Heyang Zhou, Qianqing Yang, Lingmei Kong, Yan Li |
| Key Laboratory of Medicinal Chemistry for Natural Resource, Yunnan Key Laboratory of Research and Development for Natural Products, School of Pharmacy, Ministry of Education, Yunnan University, Kunming, 650500, People's Republic of China |
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Abstract Phosphoinositide 3-kinase (PI3Ks) are lipid kinases widely involved in cell proliferation, metastasis and differentiation. Constitutive activation of the PI3K/Akt/mTOR signaling are well confirmed in colorectal cancers (CRCs). In this study, we identified isopropyl 9-ethyl-1-(naphthalen-1-yl)-9 H-pyrido[3,4-b] indole-3-carboxylate (Z86), as a novel PI3Kα inhibitor with the IC50 value of 4.28 μM. The binding of Z86 to PI3Kα was further confirmed with DARTS and CETSA assay. Immunofluorescence analysis and western blotting data demonstrated that Z86 effectively attenuated PI3K/AKT pathway. Z86 caused dramatic proliferation inhibition of CRCs through G0/G1 cycle arrest rather than apoptosis induction. Besides, the migration of CRCs was also relieved by Z86. The present study not only identified Z86 as a novel PI3Kα inhibitor with potent inhibitory efficiency on PI3K-mediated CRCs growth and migration, but also elucidated a reasonable molecular mechanism of Z86 in the Wnt signaling pathway inhibition.
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| Keywords
Colorectal cancer
PI3K
Z86
Proliferation
Cell cycle arrest
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| Fund:We thank Dr Hongbo Qin (Yunnan Minzu University) for the synthetic support. This study was funded by the National Natural Science Foundation of China (No. 32260159, 82360725, 81960738), the Yunnan Fundamental Research Projects (202301AS070022), Yunnan University (start-up grant to Y.L. and L.K.), the Central Guidance on Local Science and Technology Development Fund of Yunnan Province (202207AB110002), National Key R&D Program of China (2019YFE0109200), the central government guides local science and technology development fund (202207AA110007), the Yunnan Young & Elite Talents Project (YNWR-QNBJ-2020-084), the Youth Innovation Promotion Association CAS (to L.K.). |
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Corresponding Authors:
Lingmei Kong,E-mail:konglingmei@ynu.edu.cn;Yan Li,E-mail:yan.li@ynu.edu.cn
E-mail: konglingmei@ynu.edu.cn;yan.li@ynu.edu.cn
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Issue Date: 19 February 2024
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[1] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.
[2] Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33.
[3] Hubbard JM, Grothey A. Colorectal cancer in 2014: progress in defining first-line and maintenance therapies. Nat Rev Clin Oncol. 2015;12(2):73–4.
[4] Schmoll HJ, Stein A. Colorectal cancer in 2013: towards improved drugs, combinations and patient selection. Nat Rev Clin Oncol. 2014;11(2):79–80.
[5] Kerr D. Clinical development of gene therapy for colorectal cancer. Nat Rev Cancer. 2003;3(8):615–22.
[6] Whitehall VL, Rickman C, Bond CE, Ramsnes I, Greco SA, Umapathy A, McKeone D, Faleiro RJ, Buttenshaw RL, Worthley DL, et al. Oncogenic PIK3CA mutations in colorectal cancers and polyps. Int J Cancer. 2012;131(4):813–20.
[7] Narayanankutty A. PI3K/Akt/mTOR pathway as a therapeutic target for colorectal cancer: a review of preclinical and clinical evidence. Curr Drug Targets. 2019;20(12):1217–26.
[8] Moafian Z, Maghrouni A, Soltani A, Hashemy SI. Cross-talk between non-coding RNAs and PI3K/AKT/mTOR pathway in colorectal cancer. Mol Biol Rep. 2021;48(5):4797–811.
[9] Li S, Cheng X, Wang C. A review on traditional uses, phytochemistry, pharmacology, pharmacokinetics and toxicology of the genus Peganum. J Ethnopharmacol. 2017;203:127–62.
[10] Khan H, Patel S, Kamal MA. Pharmacological and toxicological profile of harmane-beta-carboline alkaloid: friend or foe. Curr Drug Metab. 2017;18(9):853–7.
[11] Farouk L, Laroubi A, Aboufatima R, Benharref A, Chait A. Evaluation of the analgesic effect of alkaloid extract of Peganum harmala L.: possible mechanisms involved. J Ethnopharmacol. 2008;115(3):449–54.
[12] Abbassi R, Johns TG, Kassiou M, Munoz L. DYRK1A in neurodegeneration and cancer: molecular basis and clinical implications. Pharmacol Ther. 2015;151:87–98.
[13] Li X, Bai B, Liu L, Ma P, Kong L, Yan J, Zhang J, Ye Z, Zhou H, Mao B, et al. Novel beta-carbolines against colorectal cancer cell growth via inhibition of Wnt/beta-catenin signaling. Cell Death Discov. 2015;1:15033.
[14] Lomenick B, Olsen RW, Huang J. Identification of direct protein targets of small molecules. ACS Chem Biol. 2011;6(1):34–46.
[15] Tu Y, Tan L, Tao H, Li Y, Liu H. CETSA and thermal proteome profiling strategies for target identification and drug discovery of natural products. Phytomedicine. 2023;116:154862.
[16] Sanchez TW, Ronzetti MH, Owens AE, Antony M, Voss T, Wallgren E, Talley D, Balakrishnan K, Leyes Porello SE, Rai G, et al. Real-time cellular thermal shift assay to monitor target engagement. ACS Chem Biol. 2022;17(9):2471–82.
[17] King D, Yeomanson D, Bryant HE. PI3King the lock: targeting the PI3K/Akt/mTOR pathway as a novel therapeutic strategy in neuroblastoma. J Pediatr Hematol Oncol. 2015;37(4):245–51.
[18] Li X, Wu C, Chen N, Gu H, Yen A, Cao L, Wang E, Wang L. PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget. 2016;7(22):33440–50.
[19] Lee JJ, Loh K, Yap YS. PI3K/Akt/mTOR inhibitors in breast cancer. Cancer Biol Med. 2015;12(4):342–54.
[20] Culjkovic B, Tan K, Orolicki S, Amri A, Meloche S, Borden KL. The eIF4E RNA regulon promotes the akt signaling pathway. J Cell Biol. 2008;181(1):51–63.
[21] Qie S, Diehl JA. Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med (Berl). 2016;94(12):1313–26.
[22] Xu H, Wang Y, Han Y, Wu Y, Wang J, Xu B. CDK4/6 inhibitors versus PI3K/AKT/mTOR inhibitors in women with hormone receptor-positive, HER2-negative metastatic Breast cancer: an updated systematic review and network meta-analysis of 28 randomized controlled trials. Front Oncol. 2022;12:956464.
[23] Wei R, Xiao Y, Song Y, Yuan H, Luo J, Xu W. FAT4 regulates the EMT and autophagy in colorectal cancer cells in part via the PI3K-AKT signaling axis. J Exp Clin Cancer Res. 2019;38(1):112.
[24] Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL. Phosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem. 2000;275(47):36803–10.
[25] Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A. The transcription factor slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with snail and E47 repressors. J Cell Sci. 2003;116(Pt 3):499–511.
[26] Xue G, Restuccia DF, Lan Q, Hynx D, Dirnhofer S, Hess D, Ruegg C, Hemmings BA. Akt/PKB-mediated phosphorylation of Twist1 promotes tumor metastasis via mediating cross-talk between PI3K/Akt and TGF-beta signaling axes. Cancer Discov. 2012;2(3):248–59.
[27] Zhang J, Roberts TM, Shivdasani RA. Targeting PI3K signaling as a therapeutic approach for colorectal cancer. Gastroenterology. 2011;141(1):50–61.
[28] van Engeland M, Roemen GM, Brink M, Pachen MM, Weijenberg MP, de Bruine AP, Arends JW, van den Brandt PA, de Goeij AF, Herman JG. K-ras mutations and RASSF1A promoter methylation in colorectal cancer. Oncogene. 2002;21(23):3792–5.
[29] Yost C, Torres M, Miller JR, Huang E, Kimelman D, Moon RT. The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev. 1996;10(12):1443–54.
[30] Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296(5573):1655–7.
[31] Yaguchi S, Fukui Y, Koshimizu I, Yoshimi H, Matsuno T, Gouda H, Hirono S, Yamazaki K, Yamori T. Antitumor activity of ZSTK474, a new phosphatidylinositol 3-kinase inhibitor. J Natl Cancer Inst. 2006;98(8):545–56.
[32] Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chene P, De Pover A, Schoemaker K, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 2008;7(7):1851–63.
[33] Xin P, Li C, Zheng Y, Peng Q, Xiao H, Huang Y, Zhu X. Efficacy of the dual PI3K and mTOR inhibitor NVP-BEZ235 in combination with imatinib mesylate against chronic myelogenous Leukemia cell lines. Drug Des Devel Ther. 2017;11:1115–26.
[34] Kwon YJ, Baek HS, Ye DJ, Shin S, Kim D, Chun YJ. CYP1B1 enhances cell proliferation and metastasis through induction of EMT and activation of Wnt/beta-catenin signaling via Sp1 upregulation. PLoS ONE. 2016;11(3):e0151598.
[35] Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96.
[36] Zhou H, Yu C, Kong L, Xu X, Yan J, Li Y, An T, Gong L, Gong Y, Zhu H, et al. B591, a novel specific pan-PI3K inhibitor, preferentially targets cancer stem cells. Oncogene. 2019;38(18):3371–86.
[37] Pai MY, Lomenick B, Hwang H, Schiestl R, McBride W, Loo JA, Huang J. Drug affinity responsive target stability (DARTS) for small-molecule target identification. Methods Mol Biol. 2015;1263:287–98. |
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