p-Coumaric Acid Inhibits Osteosarcoma Growth by Inhibiting PI3K/Akt Signaling Pathway


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Abstract

Background: Background: P-coumaric acid (p-CA) is a kind of phenylpropionic acid derived from aromatic amino acids, which is widely distributed in many plants and human diets. It has strong pharmacological and inhibitory effects on a variety of tumors. However, the role of p-CA in osteosarcoma, a tumor with a poor prognosis, is still unknown. Therefore, we aimed to evaluate the effect of p-CA on osteosarcoma and explore its potential mechanism.

Objective: This study aimed to investigate whether p-CA has an inhibitory effect on the growth of osteosarcoma cells and explore its potential mechanism.

Methods: Methods: MTT assay and clonogenic assay were used to detect the effect of p-CA on the proliferation of osteosarcoma cells. The effect of p-CA on apoptosis of osteosarcoma cells was detected by the Hoechst staining and flow cytometry. The effects of p-CA on the migration and invasion of osteosarcoma cells were detected by scratch healing assay and Transwell invasion assay. Western blot and PI3K/Akt pathway activator 740Y-P were used to detect the anti-tumor mechanism of p-CA on osteosarcoma cells. The effect of p-CA on osteosarcoma cells in vivo was verified by an orthotopic osteosarcoma tumor animal model in nude mice.

Results: MTT assay and clonogenic assay showed that p-CA inhibited the proliferation of osteosarcoma cells. Hoechst stain and flow cytometry showed that p-CA could induce apoptosis of osteosarcoma cells and lead to G2 phase arrest of osteosarcoma cells. Transwell assay and scratch healing assay found that p-CA could inhibit the migration and invasion of osteosarcoma cells. Western blot showed that p-CA could inhibit the activity of the PI3K/Akt signaling pathway in osteosarcoma cells, and 740Y-P could reverse its inhibitory effect. In vivo mouse models, p-CA has an antitumor effect on osteosarcoma cells in vivo, and at the same time, it has less toxic side effects on mice.

Conclusion: This study demonstrated that p-CA could effectively inhibit the proliferation, migration and invasion of osteosarcoma cells and promote apoptosis. p-CA may play an anti-osteosarcoma role by inhibiting PI3K/Akt signaling pathway.

About the authors

Bo Yang

Department of Handsurgery, 521 Hospital of Norinco Group

Email: info@benthamscience.net

Bowen Wang

Department of Handsurgery, 521 Hospital of Norinco Group

Email: info@benthamscience.net

Guoliang Wang

Department of Handsurgery, 521 Hospital of Norinco Group

Email: info@benthamscience.net

Wenliang Cao

Department of Handsurgery, 521 Hospital of Norinco Group

Email: info@benthamscience.net

Qian Wang

Department of Handsurgery, 521 Hospital of Norinco Group

Email: info@benthamscience.net

Hao Pu

Department of Orthopaedics, Xi'an ji ren Hospital

Email: info@benthamscience.net

Wei An

Department of Handsurgery, 521 Hospital of Norinco Group

Author for correspondence.
Email: info@benthamscience.net

References

  1. Ottaviani, G.; Jaffe, N. The epidemiology of osteosarcoma. Cancer Treat Res, 2009, 152, 3-13. doi: 10.1007/978-1-4419-0284-9_1
  2. Rather, H.A.; Jhala, D.; Vasita, R. Dual functional approaches for osteogenesis coupled angiogenesis in bone tissue engineering. Mater. Sci. Eng. C, 2019, 103, 109761. doi: 10.1016/j.msec.2019.109761 PMID: 31349418
  3. Hauben, E.I.; Arends, J.; Vandenbroucke, J.P.; van Asperen, C.J.; Van Marck, E.; Hogendoorn, P.C.W. Multiple primary malignancies in osteosarcoma patients. Incidence and predictive value of osteosarcoma subtype for cancer syndromes related with osteosarcoma. Eur. J. Hum. Genet., 2003, 11(8), 611-618. doi: 10.1038/sj.ejhg.5201012 PMID: 12891382
  4. Hayden, J.B.; Hoang, B.H. Osteosarcoma: Basic science and clinical implications. Orthop. Clin. North Am., 2006, 37(1), 1-7. doi: 10.1016/j.ocl.2005.06.004 PMID: 16311106
  5. Chen, Y.; Cao, J.; Zhang, N.; Yang, B.; He, Q.; Shao, X.; Ying, M. Advances in differentiation therapy for osteosarcoma. Drug Discov. Today, 2020, 25(3), 497-504. doi: 10.1016/j.drudis.2019.08.010 PMID: 31499188
  6. Hattinger, C.M.; Fanelli, M.; Tavanti, E.; Vella, S.; Ferrari, S.; Picci, P.; Serra, M. Advances in emerging drugs for osteosarcoma. Expert Opin. Emerg. Drugs, 2015, 20(3), 495-514. doi: 10.1517/14728214.2015.1051965 PMID: 26021401
  7. Yin, C.; Dai, X.; Huang, X.; Zhu, W.; Chen, X.; Zhou, Q.; Wang, C.; Zhao, C.; Zou, P.; Liang, G.; Rajamanickam, V.; Wang, O.; Zhang, X.; Cui, R. Alantolactone promotes ER stress-mediated apoptosis by inhibition of TrxR1 in triple-negative breast cancer cell lines and in a mouse model. J. Cell. Mol. Med., 2019, 23(3), 2194-2206. doi: 10.1111/jcmm.14139 PMID: 30609207
  8. He, W.; Xia, Y.; Cao, P.; Hong, L.; Zhang, T.; Shen, X.; Zheng, P.; Shen, H.; Liang, G.; Zou, P. Curcuminoid WZ35 synergize with cisplatin by inducing ROS production and inhibiting TrxR1 activity in gastric cancer cells. J. Exp. Clin. Cancer Res., 2019, 38(1), 207. doi: 10.1186/s13046-019-1215-y PMID: 31113439
  9. Pei, K.; Ou, J.; Huang, J.; Ou, S. p -Coumaric acid and its conjugates: Dietary sources, pharmacokinetic properties and biological activities. J. Sci. Food Agric., 2016, 96(9), 2952-2962. doi: 10.1002/jsfa.7578 PMID: 26692250
  10. Pragasam, S.J.; Venkatesan, V.; Rasool, M. Immunomodulatory and anti-inflammatory effect of p-coumaric acid, a common dietary polyphenol on experimental inflammation in rats. Inflammation, 2013, 36(1), 169-176. doi: 10.1007/s10753-012-9532-8 PMID: 22923003
  11. Alam, M.A.; Subhan, N.; Hossain, H.; Hossain, M.; Reza, H.M.; Rahman, M.M.; Ullah, M.O. Hydroxycinnamic acid derivatives: A potential class of natural compounds for the management of lipid metabolism and obesity. Nutr. Metab., 2016, 13(1), 27. doi: 10.1186/s12986-016-0080-3 PMID: 27069498
  12. Tehami, W.; Nani, A.; Khan, N.A.; Hichami, A. New insights into the anticancer effects of p -Coumaric Acid: Focus on colorectal cancer. Dose Response, 2023, 21(1) doi: 10.1177/15593258221150704 PMID: 36636631
  13. Oliva, M.A.; Castaldo, S.; Rotondo, R.; Staffieri, S.; Sanchez, M.; Arcella, A. Inhibiting effect of p -Coumaric acid on U87MG human glioblastoma cell growth. J. Chemother., 2022, 34(3), 173-183. doi: 10.1080/1120009X.2021.1953888 PMID: 34424147
  14. Kolahi, M.; Saremi, S.; Tabandeh, M.; Hashemitabar, M. Induction of apoptosis and suppression of Ras gene expression in MCF human breast cancer cells. J. Cancer Res. Ther., 2022, 18(4), 1052-1060. doi: 10.4103/jcrt.JCRT_624_20 PMID: 36149161
  15. Mirabello, L.; Troisi, R.J.; Savage, S.A. Osteosarcoma incidence and survival rates from 1973 to 2004. Cancer, 2009, 115(7), 1531-1543. doi: 10.1002/cncr.24121 PMID: 19197972
  16. Xiao, X.; Zhang, Y.; Pan, W.; Chen, F. miR-139-mediated NOTCH1 regulation is crucial for the inhibition of osteosarcoma progression caused by resveratrol. Life Sci., 2020, 242, 117215. doi: 10.1016/j.lfs.2019.117215 PMID: 31881225
  17. Ritter, J.; Bielack, S.S. Osteosarcoma. Ann. Oncol., 2010, 21(S7), vii320-vii325. doi: 10.1093/annonc/mdq276 PMID: 20943636
  18. Hattinger, C.M.; Pasello, M.; Ferrari, S.; Picci, P.; Serra, M. Emerging drugs for high-grade osteosarcoma. Expert Opin. Emerg. Drugs, 2010, 15(4), 615-634. doi: 10.1517/14728214.2010.505603 PMID: 20690888
  19. Lou, Y.; Guo, Z.; Zhu, Y.; Kong, M.; Zhang, R.; Lu, L.; Wu, F.; Liu, Z.; Wu, J. Houttuynia cordata Thunb. and its bioactive compound 2-undecanone significantly suppress benzo(a)pyrene-induced lung tumorigenesis by activating the Nrf2-HO-1/NQO-1 signaling pathway. J. Exp. Clin. Cancer Res., 2019, 38(1), 242. doi: 10.1186/s13046-019-1255-3 PMID: 31174565
  20. Park, S.Y.; Jeong, M.S.; Han, C.W.; Yu, H.S.; Jang, S.B. Structural and functional insight into proliferating cell nuclear antigen. J. Microbiol. Biotechnol., 2016, 26(4), 637-647. doi: 10.4014/jmb.1509.09051 PMID: 26699741
  21. Strzalka, W.; Ziemienowicz, A. Proliferating cell nuclear antigen (PCNA): A key factor in DNA replication and cell cycle regulation. Ann. Bot., 2011, 107(7), 1127-1140. doi: 10.1093/aob/mcq243 PMID: 21169293
  22. Zheng, J.; Li, Q.; Wang, W.; Wang, Y.; Fu, X.; Wang, W.; Fan, L.; Yan, W. Apoptosis-related protein-1 acts as a tumor suppressor in cholangiocarcinoma cells by inducing cell cycle arrest via downregulation of cyclin-dependent kinase subunits. Oncol. Rep., 2016, 35(2), 809-816. doi: 10.3892/or.2015.4422 PMID: 26572808
  23. Zhang, Z.; Zheng, Y.; Zhu, R.; Zhu, Y.; Yao, W.; Liu, W.; Gao, X. The ERK/eIF4F/Bcl-XL pathway mediates SGP-2 induced osteosarcoma cells apoptosis in vitro and in vivo. Cancer Lett., 2014, 352(2), 203-213. doi: 10.1016/j.canlet.2014.06.015 PMID: 25025927
  24. Igney, F.H.; Krammer, P.H. Death and anti-death: Tumour resistance to apoptosis. Nat. Rev. Cancer, 2002, 2(4), 277-288. doi: 10.1038/nrc776 PMID: 12001989
  25. Parrish, A.B.; Freel, C.D.; Kornbluth, S. Cellular mechanisms controlling caspase activation and function. Cold Spring Harb. Perspect. Biol., 2013, 5(6), a008672. doi: 10.1101/cshperspect.a008672 PMID: 23732469
  26. White, K.; Arama, E.; Hardwick, J.M. Controlling caspase activity in life and death. PLoS Genet., 2017, 13(2), e1006545. doi: 10.1371/journal.pgen.1006545 PMID: 28207784
  27. Xu, P.; Cai, X.; Zhang, W.; Li, Y.; Qiu, P.; Lu, D.; He, X. Flavonoids of rosa roxburghii tratt exhibit radioprotection and anti-apoptosis properties via the Bcl-2(Ca2+)/Caspase-3/PARP-1 pathway. Apoptosis, 2016, 21(10), 1125-1143. doi: 10.1007/s10495-016-1270-1 PMID: 27401922
  28. Mohan, V.; Agarwal, R.; Singh, R.P. A novel alkaloid, evodiamine causes nuclear localization of cytochrome-c and induces apoptosis independent of p53 in human lung cancer cells. Biochem. Biophys. Res. Commun., 2016, 477(4), 1065-1071. doi: 10.1016/j.bbrc.2016.07.037 PMID: 27402273
  29. Ehnman, M.; Chaabane, W.; Haglund, F.; Tsagkozis, P. The tumor microenvironment of pediatric sarcoma: Mesenchymal mechanisms regulating cell migration and metastasis. Curr. Oncol. Rep., 2019, 21(10), 90. doi: 10.1007/s11912-019-0839-6 PMID: 31418125
  30. Pastushenko, I.; Blanpain, C. EMT transition states during tumor progression and metastasis. Trends Cell Biol., 2019, 29(3), 212-226. doi: 10.1016/j.tcb.2018.12.001 PMID: 30594349
  31. Skrzypek, K.; Majka, M. Interplay among SNAIL transcription factor, microRNAs, long non-coding RNAs, and Circular RNAs in the regulation of tumor growth and metastasis. Cancers, 2020, 12(1), 209. doi: 10.3390/cancers12010209 PMID: 31947678
  32. Wang, Y.; Shi, J.; Chai, K.; Ying, X.; Zhou, B. The role of snail in EMT and tumorigenesis. Curr. Cancer Drug Targets, 2013, 13(9), 963-972. doi: 10.2174/15680096113136660102 PMID: 24168186
  33. Mendonsa, A.M.; Na, T.Y.; Gumbiner, B.M. E-cadherin in contact inhibition and cancer. Oncogene, 2018, 37(35), 4769-4780. doi: 10.1038/s41388-018-0304-2 PMID: 29780167
  34. Satelli, A.; Li, S. Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell. Mol. Life Sci., 2011, 68(18), 3033-3046. doi: 10.1007/s00018-011-0735-1 PMID: 21637948
  35. Kapoor, C.; Vaidya, S.; Wadhwan, V. Hitesh; Kaur, G.; Pathak, A. Seesaw of matrix metalloproteinases (MMPs). J. Cancer Res. Ther., 2016, 12(1), 28-35. doi: 10.4103/0973-1482.157337 PMID: 27072206
  36. Zhang, H.; Jiang, H.; Zhang, H.; Liu, J.; Hu, X.; Chen, L. Anti-tumor efficacy of phellamurin in osteosarcoma cells: Involvement of the PI3K/AKT/mTOR pathway. Eur. J. Pharmacol., 2019, 858, 172477. doi: 10.1016/j.ejphar.2019.172477 PMID: 31228450
  37. Zhang, X.; Qu, P.; Zhao, H.; Zhao, T.; Cao, N. COX 2 promotes epithelial mesenchymal transition and migration in osteosarcoma MG 63 cells via PI3K/AKT/NF κB signaling. Mol. Med. Rep., 2019, 20(4), 3811-3819. doi: 10.3892/mmr.2019.10598 PMID: 31485669
  38. Yang, H.L.; Thiyagarajan, V.; Shen, P.C.; Mathew, D.C.; Lin, K.Y.; Liao, J.W.; Hseu, Y.C. Anti-EMT properties of CoQ0 attributed to PI3K/AKT/NFKB/MMP-9 signaling pathway through ROS-mediated apoptosis. J. Exp. Clin. Cancer Res., 2019, 38(1), 186. doi: 10.1186/s13046-019-1196-x PMID: 31068208
  39. Yang, Q.; Jiang, W.; Hou, P. Emerging role of PI3K/AKT in tumor-related epigenetic regulation. Semin. Cancer Biol., 2019, 59(1), 112-124. doi: 10.1016/j.semcancer.2019.04.001 PMID: 30951826
  40. Revathidevi, S.; Munirajan, A.K. Akt in cancer: Mediator and more. Semin. Cancer Biol., 2019, 59(1), 80-91. doi: 10.1016/j.semcancer.2019.06.002 PMID: 31173856
  41. Huang, H.; Lu, Q.; Yuan, X.; Zhang, P.; Ye, C.; Wei, M.; Yang, C.; Zhang, L.; Huang, Y.; Luo, X.; Luo, J. Andrographolide inhibits the growth of human osteosarcoma cells by suppressing Wnt/β-catenin, PI3K/AKT and NF-κB signaling pathways. Chem. Biol. Interact., 2022, 365, 110068. doi: 10.1016/j.cbi.2022.110068 PMID: 35917943
  42. Alzahrani, A.S. PI3K/Akt/MTOR inhibitors in cancer: At the bench and bedside. Semin. Cancer Biol., 2019, 59, 125-132. doi: 10.1016/j.semcancer.2019.07.009

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