Low-frequency Ultrasound Enhances Chemotherapy Sensitivity and Induces Autophagy in PTX-resistant PC-3 Cells Via the Endoplasmic Reticulum Stress-mediated PI3K/Akt/mTOR Signaling Pathway

Overview

Journal Onco Targets Ther

Publisher Dove Medical Press

Specialty Oncology

Date 2018 Sep 27

PMID 30254455

Citations 19

Authors

Yuqi Wu

Xiaobing Liu

Zizhen Qin

Li Hu

Xiangwei Wang

Affiliations

Soon will be listed here.

Abstract

Background: Sonodynamic therapy (SDT) is an emerging tumor-inhibiting method that has gained attention in cancer therapy in the last several years. Although autophagy has been observed in SDT-treated cancer cells, its role and mechanism of action remain unclear. This study aimed to investigate the effects of low-frequency ultrasound on autophagy and drug-resistance of paclitaxel (PTX)-resistant PC-3 cells via the endoplasmic reticulum stress (ERs)-mediated PI3K/AT/mTOR signaling pathway.

Methods: CCK-8 assay was conducted to select the appropriate exposure time for PTX-resistant PC-3 cells under low-frequency ultrasound. PTX-resistant PC-3 cells were divided into a control group, PTX group, ultrasound group, ultrasound + PTX group, ultrasound + PTX + autophagy-related gene 5 (Atg5) siRNA group, and ultrasound + 4-PBA (an ERs inhibitor) group. Autophagy was observed by transmission electron microscopy (TEM) and fluorescence microscopy. Cell proliferation was evaluated using CCK-8 assay; apoptosis was detected by flow cytometry. Expression of multiple drug-resistance genes was detected by qRT-PCR. Western blotting was used to detect the expression of ERS-related proteins, autophagy-related proteins, apoptosis-related proteins, and PI3K/AKT/mTOR pathway-related proteins.

Results: Ten-second exposure was selected as optimal for all experiments. Compared to the PTX group, the level of autophagy, inhibition rate, apoptosis rate, and expression of ERS-related proteins (GRP78) increased, whereas the expression of multiple drug-resistance genes (, , and ), PI3K/AKT/mTOR pathway-related proteins (PI3K, p-AKT, mTORC1), and apoptosis-related proteins (Bcl-2, NF-κB) decreased in PTX-resistant PC-3 cells after low-frequency ultrasound and PTX treatment for 24 h. These trends were more obvious after treatment with Atg5 siRNA, excluding the autophagy level. Post 4-PBA-treatment, the expression of GRP78 and LC3II proteins decreased, whereas that of PI3K, p-AKT, and mTORC1 increased.

Conclusion: Results indicated that ultrasound induces autophagy by ERs-mediated PI3K/AKT/mTOR signaling pathway in PTX-resistant PC-3 cells; this autophagy acts as a cytoprotector during low-frequency ultrasound-mediated reversal of drug resistance.

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References

Chandrika G, Natesh K, Ranade D, Chugh A, Shastry P . Suppression of the invasive potential of Glioblastoma cells by mTOR inhibitors involves modulation of NFκB and PKC-α signaling. Sci Rep. 2016; 6:22455. PMC: 4778030. DOI: 10.1038/srep22455. View

Gump J, Thorburn A . Autophagy and apoptosis: what is the connection?. Trends Cell Biol. 2011; 21(7):387-92. PMC: 3539742. DOI: 10.1016/j.tcb.2011.03.007. View

Siegel R, Miller K, Jemal A . Cancer statistics, 2018. CA Cancer J Clin. 2018; 68(1):7-30. DOI: 10.3322/caac.21442. View

Mohamed E, Cao Y, Rodriguez P . Endoplasmic reticulum stress regulates tumor growth and anti-tumor immunity: a promising opportunity for cancer immunotherapy. Cancer Immunol Immunother. 2017; 66(8):1069-1078. PMC: 5700458. DOI: 10.1007/s00262-017-2019-6. View

Amaravadi R, Kimmelman A, White E . Recent insights into the function of autophagy in cancer. Genes Dev. 2016; 30(17):1913-30. PMC: 5066235. DOI: 10.1101/gad.287524.116. View

Wang P, Leung A, Xu C . Low-intensity ultrasound-induced cellular destruction and autophagy of nasopharyngeal carcinoma cells. Exp Ther Med. 2012; 2(5):849-852. PMC: 3440834. DOI: 10.3892/etm.2011.317. View

Ranjan A, German N, Mikelis C, Srivenugopal K, Srivastava S . Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer. Tumour Biol. 2017; 39(6):1010428317705517. DOI: 10.1177/1010428317705517. View

Wang Y, Chen Y, Zhang W, Yang Y, Shen E, Hu B . Upregulation of Beclin-1 expression in DU-145 cells following low-frequency ultrasound irradiation combined with microbubbles. Oncol Lett. 2015; 10(4):2487-2490. PMC: 4580001. DOI: 10.3892/ol.2015.3509. View

Frulio N, Trillaud H, Deckers R, Lepreux S, Moonen C, Quesson B . Influence of ultrasound induced cavitation on magnetic resonance imaging contrast in the rat liver in the presence of macromolecular contrast agent. Invest Radiol. 2010; 45(5):282-7. DOI: 10.1097/RLI.0b013e3181dac2a7. View

10.

Ruf S, Heberle A, Langelaar-Makkinje M, Gelino S, Wilkinson D, Gerbeth C . PLK1 (polo like kinase 1) inhibits MTOR complex 1 and promotes autophagy. Autophagy. 2017; 13(3):486-505. PMC: 5361591. DOI: 10.1080/15548627.2016.1263781. View

11.

Mabuchi S, Kuroda H, Takahashi R, Sasano T . The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer. Gynecol Oncol. 2015; 137(1):173-9. DOI: 10.1016/j.ygyno.2015.02.003. View

12.

Bao G, Li C, Qi L, Wang N, He B . Tetrandrine protects against oxygen-glucose-serum deprivation/reoxygenation-induced injury via PI3K/AKT/NF-κB signaling pathway in rat spinal cord astrocytes. Biomed Pharmacother. 2016; 84:925-930. DOI: 10.1016/j.biopha.2016.10.007. View

13.

Yang N, Qu Y, Cheng Y, Liang T, Zhang M, Zhang D . Endoplasmic reticulum stress regulates proliferation, migration and invasion of human ovarian cancer SKOV3 cells through PI3K/AKT/mTOR signaling pathway. Cancer Biomark. 2017; 19(3):263-269. DOI: 10.3233/CBM-160424. View

14.

Iurlaro R, Munoz-Pinedo C . Cell death induced by endoplasmic reticulum stress. FEBS J. 2015; 283(14):2640-52. DOI: 10.1111/febs.13598. View

15.

Wang X, Jia Y, Su X, Wang P, Zhang K, Feng X . Combination of Protoporphyrin IX-mediated Sonodynamic Treatment with Doxorubicin Synergistically Induced Apoptotic Cell Death of a Multidrug-Resistant Leukemia K562/DOX Cell Line. Ultrasound Med Biol. 2015; 41(10):2731-9. DOI: 10.1016/j.ultrasmedbio.2015.06.001. View

16.

Costley D, Mc Ewan C, Fowley C, McHale A, Atchison J, Nomikou N . Treating cancer with sonodynamic therapy: a review. Int J Hyperthermia. 2015; 31(2):107-17. DOI: 10.3109/02656736.2014.992484. View

17.

Bertacchini J, Heidari N, Mediani L, Capitani S, Shahjahani M, Ahmadzadeh A . Targeting PI3K/AKT/mTOR network for treatment of leukemia. Cell Mol Life Sci. 2015; 72(12):2337-47. PMC: 11113278. DOI: 10.1007/s00018-015-1867-5. View

18.

Zou Y, Li Q, Jiang L, Guo C, Li Y, Yu Y . DNA Hypermethylation of CREB3L1 and Bcl-2 Associated with the Mitochondrial-Mediated Apoptosis via PI3K/Akt Pathway in Human BEAS-2B Cells Exposure to Silica Nanoparticles. PLoS One. 2016; 11(6):e0158475. PMC: 4928798. DOI: 10.1371/journal.pone.0158475. View

19.

Zhang W, Wan X, Liu Z, Xiao L, Huang H, Liu X . The emerging role of oxidative stress in regulating autophagy: applications of cancer therapy. Cell Mol Biol (Noisy-le-grand). 2017; 63(4):67-76. DOI: 10.14715/cmb/2017.63.4.11. View

20.

Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T . EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer. Eur Urol. 2016; 71(4):630-642. DOI: 10.1016/j.eururo.2016.08.002. View