Propofol may increase caspase and MAPK pathways, and suppress the Akt pathway to induce apoptosis in MA‑10 mouse Leydig tumor cells

  • Authors:
    • Fu‑Chi Kang
    • Shu‑Chun Wang
    • Edmund Cheung So
    • Ming‑Min Chang
    • Kar‑Lok Wong
    • Ka Shun Cheng
    • Yung‑Chia Chen
    • Bu‑Miin Huang
  • View Affiliations

  • Published online on: April 18, 2019     https://doi.org/10.3892/or.2019.7129
  • Pages: 3565-3574
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

In the western world, there is an increasing trend of occurrence in testicular cancer. Treatment of malignant testicular cancer is primarily combined surgery with various chemical drugs. Propofol has been frequently used as an anesthetic and sedative induction agent, which could modulate different γ‑aminobutyric acid receptors in the central nervous system. Studies demonstrated that propofol activates endoplasmic reticulum stress to induce apoptosis in lung cancer. However, it remains elusive whether propofol regulates caspase and/or mitogen‑activated protein kinase (MAPK) pathways to induce apoptosis in Leydig tumor cells. In the present study, MA‑10 mouse Leydig tumor cells were treated with propofol, and possible signal pathways associated with apoptosis were investigated. Results demonstrated that increasing dosage of propofol (300‑600 µM) for 24 h significantly decreased cell viability in MA‑10 cells (P<0.05). In flow cytometry analysis, the amount of sub‑G1 phase cell numbers in MA‑10 cells was significantly increased by propofol (P<0.05). Additionally, Annexin V/propidium iodide double staining further confirmed that propofol could induce MA‑10 cell apoptosis. Furthermore, cleaved caspase‑8, ‑9 and ‑3, and/or poly(ADP‑ribose) polymerase were significantly activated following treatment of propofol in MA‑10 cells. In addition, c‑Jun N‑terminal kinase, extracellular signal‑regulated kinase 1/2, and p38 were significantly activated by propofol in MA‑10 cells (P<0.05), indicating that propofol may induce apoptosis through the MAPK pathway. Additionally, propofol diminished the phosphorylation of Akt to activate apoptosis in MA‑10 cells. In conclusion, propofol may induce MA‑10 cell apoptosis by activating caspase and MAPK pathways, and inhibiting the Akt pathway in MA‑10 cells, demonstrating that propofol may be a potential anticancer agent against Leydig cell cancer.

References

1 

Busettini C and Frolich MA: Effects of mild to moderate sedation on saccadic eye movements. Behav Brain Res. 272:286–302. 2014. View Article : Google Scholar : PubMed/NCBI

2 

Cassinello F, Prieto I, Del Olmo M, Rivas S and Strichartz GR: Cancer surgery: How may anesthesia influence outcome? J Clin Anesth. 27:262–272. 2015. View Article : Google Scholar : PubMed/NCBI

3 

Wang P, Chen J, Mu LH, Du QH, Niu XH and Zhang MY: Propofol inhibits invasion and enhances paclitaxel- induced apoptosis in ovarian cancer cells through the suppression of the transcription factor slug. Eur Rev Med Pharmacol Sci. 17:1722–1729. 2013.PubMed/NCBI

4 

Ye Z, Jingzhong L, Yangbo L, Lei C and Jiandong Y: Propofol inhibits proliferation and invasion of osteosarcoma cells by regulation of microRNA-143 expression. Oncol Res. 21:201–207. 2013. View Article : Google Scholar : PubMed/NCBI

5 

Du QH, Xu YB, Zhang MY, Yun P and He CY: Propofol induces apoptosis and increases gemcitabine sensitivity in pancreatic cancer cells in vitro by inhibition of nuclear factor-kappaB activity. World J Gastroenterol. 19:5485–5492. 2013. View Article : Google Scholar : PubMed/NCBI

6 

Cui WY, Liu Y, Zhu YQ, Song T and Wang QS: Propofol induces endoplasmic reticulum (ER) stress and apoptosis in lung cancer cell H460. Tumour Biol. 35:5213–5217. 2014. View Article : Google Scholar : PubMed/NCBI

7 

Xing SG, Zhang KJ, Qu JH, Ren YD and Luan Q: Propofol induces apoptosis of non-small cell lung cancer cells via ERK1/2-dependent upregulation of PUMA. Eur Rev Med Pharmacol Sci. 22:4341–4349. 2018.PubMed/NCBI

8 

Su Z, Hou XK and Wen QP: Propofol induces apoptosis of epithelial ovarian cancer cells by upregulation of microRNA let-7i expression. Eur J Gynaecol Oncol. 35:688–691. 2014.PubMed/NCBI

9 

Liu SQ, Zhang JL, Li ZW, Hu ZH, Liu Z and Li Y: Propofol inhibits proliferation, migration, invasion and promotes apoptosis through down-regulating miR-374a in hepatocarcinoma cell lines. Cell Physiol Biochem. 49:2099–2110. 2018. View Article : Google Scholar : PubMed/NCBI

10 

Yu FX and Guan KL: The Hippo pathway: Regulators and regulations. Genes Dev. 27:355–371. 2013. View Article : Google Scholar : PubMed/NCBI

11 

Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000. View Article : Google Scholar : PubMed/NCBI

12 

Kuwabara M, Asanuma T, Niwa K and Inanami O: Regulation of cell survival and death signals induced by oxidative stress. J Clin Biochem Nutr. 43:51–57. 2008. View Article : Google Scholar : PubMed/NCBI

13 

Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, et al: Classification of cell death: Recommendations of the nomenclature committee on cell death 2009. Cell Death Differ. 16:3–11. 2009. View Article : Google Scholar : PubMed/NCBI

14 

Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B and Bao JK: Programmed cell death pathways in cancer: A review of apoptosis, autophagy and programmed necrosis. Cell Prolif. 45:487–498. 2012. View Article : Google Scholar : PubMed/NCBI

15 

Long JS and Ryan KM: New frontiers in promoting tumour cell death: Targeting apoptosis, necroptosis and autophagy. Oncogene. 31:5045–5060. 2012. View Article : Google Scholar : PubMed/NCBI

16 

Kerr JF, Wyllie AH and Currie AR: Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 26:239–257. 1972. View Article : Google Scholar : PubMed/NCBI

17 

Oliveira JB and Gupta S: Disorders of apoptosis: Mechanisms for autoimmunity in primary immunodeficiency diseases. J Clin Immunol. 28 (Suppl 1):S20–S28. 2008. View Article : Google Scholar : PubMed/NCBI

18 

Lewis-Wambi JS and Jordan VC: Estrogen regulation of apoptosis: How can one hormone stimulate and inhibit? Breast Cancer Res. 11:2062009. View Article : Google Scholar : PubMed/NCBI

19 

Cossarizza A, Baccarani-Contri M, Kalashnikova G and Franceschi C: A new method for the cytofluorimetric analysis of mitochondrial membrane potential using the J-aggregate forming lipophilic cation 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolcarbocyanine iodide (JC-1). Biochemical and biophysical research communications Biochem Biophys Res Commun. 197:40–45. 1993. View Article : Google Scholar : PubMed/NCBI

20 

Green DR and Reed JC: Mitochondria and apoptosis. Science. 281:1309–1312. 1998. View Article : Google Scholar : PubMed/NCBI

21 

Johnson GL and Lapadat R: Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 298:1911–1912. 2002. View Article : Google Scholar : PubMed/NCBI

22 

Son Y, Cheong YK, Kim NH, Chung HT, Kang DG and Pae HO: Mitogen-activated protein kinases and reactive oxygen species: How can ROS activate MAPK pathways? J Signal Transduct. 2011:7926392011. View Article : Google Scholar : PubMed/NCBI

23 

Rauch N, Rukhlenko OS, Kolch W and Kholodenko BN: MAPK kinase signalling dynamics regulate cell fate decisions and drug resistance. Curr Opin Struct Biol. 41:151–158. 2016. View Article : Google Scholar : PubMed/NCBI

24 

Markman B, Dienstmann R and Tabernero J: Targeting the PI3K/Akt/mTOR pathway-beyond rapalogs. Oncotarget. 1:530–543. 2010.PubMed/NCBI

25 

Hein AL, Ouellette MM and Yan Y: Radiation-induced signaling pathways that promote cancer cell survival (review). Int J Oncol. 45:1813–1819. 2014. View Article : Google Scholar : PubMed/NCBI

26 

Zhou C, Zhao XM, Li XF, Wang C, Zhang XT, Liu XZ, Ding XF, Xiang SL and Zhang J: Curcumin inhibits AP-2γ-induced apoptosis in the human malignant testicular germ cells in vitro. Acta Pharmacol Sin. 34:1192–1200. 2013. View Article : Google Scholar : PubMed/NCBI

27 

Pang S, Zhang L, Shi Y and Liu Y: Unclassified mixed germ cell-sex cord-stromal tumor with multiple malignant cellular elements in a young woman: A case report and review of the literature. Int J Clin Exp Pathol. 7:5259–5266. 2014.PubMed/NCBI

28 

Olivier P, Simoneau-Roy J, Francoeur D, Sartelet H, Parma J, Vassart G and Van Vliet G: Leydig cell tumors in children: Contrasting clinical, hormonal, anatomical, and molecular characteristics in boys and girls. J Pediatr. 161:1147–1152. 2012. View Article : Google Scholar : PubMed/NCBI

29 

Gheorghisan-Galateanu AA: Leydig cell tumors of the testis: A case report. BMC Res Notes. 7:6562014. View Article : Google Scholar : PubMed/NCBI

30 

Green LM, Reade JL and Ware CF: Rapid colorimetric assay for cell viability: Application to the quantitation of cytotoxic and growth inhibitory lymphokines. J Immunol Methods. 70:257–268. 1984. View Article : Google Scholar : PubMed/NCBI

31 

So EC, Chen YC, Wang SC, Wu CC, Huang MC, Lai MS, Pan BS, Kang FC and Huang BM: Midazolam regulated caspase pathway, endoplasmic reticulum stress, autophagy, and cell cycle to induce apoptosis in MA-10 mouse Leydig tumor cells. Onco Targets Ther. 9:2519–2533. 2017.

32 

Chang MM, Lai MS, Hong SY, Pan BS, Huang H, Yang SH, Wu CC, Sunny Sun H, Chuang JI, Wang CY and Huang BM: FGF9/FGFR2 increase cell proliferation by activating ERK1/2, Rb/E2F1 and cell cycle pathways in mouse Leydig tumor cells. Cancer Sci. 109:3503–3518. 2018. View Article : Google Scholar : PubMed/NCBI

33 

Kang FC, Wang SC, Chang MM, Pan BS, Wong KL, Cheng KS, So EC and Huang BM: Midazolam activates caspase, MAPKs and endoplasmic reticulum stress pathways, and inhibits cell cycle and Akt pathway, to induce apoptosis in TM3 mouse Leydig progenitor cells. Onco Targets Ther. 11:1475–1490. 2018. View Article : Google Scholar : PubMed/NCBI

34 

Lowry OH, Rosebrough NJ, Farr AL and Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem. 193:265–275. 1951.PubMed/NCBI

35 

van Engeland M, Ramaekers FC, Schutte B and Reutelingsperger CP: A novel assay to measure loss of plasma membrane asymmetry during apoptosis of adherent cells in culture. Cytometry. 24:131–139. 1996. View Article : Google Scholar : PubMed/NCBI

36 

Creagh EM and Martin SJ: Caspases: Cellular demolition experts. Biochem Soc Trans. 29:696–702. 2001. View Article : Google Scholar : PubMed/NCBI

37 

Harris CE, Grounds RM, Murray AM, Lumley J, Royston D and Morgan M: Propofol for long-term sedation in the intensive care unit. A comparison with papaveretum and midazolam. Anaesthesia. 45:366–372. 1990. View Article : Google Scholar : PubMed/NCBI

38 

Radke J: Analgesia and sedation in intensive care patients. Der Anaesthesist (German). 41:793–808. 1992.

39 

Yu D, Jiang Y, Gao J, Liu B and Chen P: Repeated exposure to propofol potentiates neuroapoptosis and long-term behavioral deficits in neonatal rats. Neurosci Lett. 534:41–46. 2013. View Article : Google Scholar : PubMed/NCBI

40 

Taylor RC, Cullen SP and Martin SJ: Apoptosis: Controlled demolition at the cellular level. Nat Rev Mol Cell Biol. 9:231–241. 2008. View Article : Google Scholar : PubMed/NCBI

41 

Paul-Samojedny M, Suchanek R, Borkowska P, Pudelko A, Owczarek A, Kowalczyk M, Machnik G, Fila-Danilow A and Kowalski J: Knockdown of AKT3 (PKBgamma) and PI3KCA suppresses cell viability and proliferation and induces the apoptosis of glioblastoma multiforme T98G cells. Biomed Res Int. 2014:7681812014. View Article : Google Scholar : PubMed/NCBI

42 

Zhang C, Chen Z, Zhou X, Xu W, Wang G, Tang X, Luo L, Tu J, Zhu Y, Hu W, et al: Cantharidin induces G/M phase arrest and apoptosis in human gastric cancer SGC-7901 and BGC-823 cells. Oncol Lett. 8:2721–2726. 2014. View Article : Google Scholar : PubMed/NCBI

43 

Khan AA, Jabeen M, Khan AA and Owais M: Anticancer efficacy of a novel propofol-linoleic acid-loaded escheriosomal formulation against murine hepatocellular carcinoma. Nanomedicine (London). 8:1281–1294. 2013. View Article : Google Scholar

44 

Hibi M, Lin A, Smeal T, Minden A and Karin M: Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 7:2135–2148. 1993. View Article : Google Scholar : PubMed/NCBI

45 

Cano E, Hazzalin CA and Mahadevan LC: Anisomycin-activated protein kinases p45 and p55 but not mitogen-activated protein kinases ERK-1 and −2 are implicated in the induction of c-fos and c-jun. Mol Cell Biol. 14:7352–7362. 1994. View Article : Google Scholar : PubMed/NCBI

46 

Shen Y, Yang J, Zhao J, Xiao C, Xu C and Xiang Y: The switch from ER stress-induced apoptosis to autophagy via ROS-mediated JNK/p62 signals: A survival mechanism in methotrexate-resistant choriocarcinoma cells. Exp Cell Res. 334:207–218. 2015. View Article : Google Scholar : PubMed/NCBI

47 

Lin X, Fang Q, Chen S, Zhe N, Chai Q, Yu M, Zhang Y, Wang Z and Wang J: Heme oxygenase-1 suppresses the apoptosis of acute myeloid leukemia cells via the JNK/c-JUN signaling pathway. Leuk Res. 39:544–552. 2015. View Article : Google Scholar : PubMed/NCBI

48 

Dhanasekaran DN and Reddy EP: JNK signaling in apoptosis. Oncogene. 27:6245–6251. 2008. View Article : Google Scholar : PubMed/NCBI

49 

Tang D, Wu D, Hirao A, Lahti JM, Liu L, Mazza B, Kidd VJ, Mak TW and Ingram AJ: ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53. J Biol Chem. 277:12710–12717. 2002. View Article : Google Scholar : PubMed/NCBI

50 

Lee JM, Lee JM, Kim KR, Im H and Kim YH: Zinc preconditioning protects against neuronal apoptosis through the mitogen-activated protein kinase-mediated induction of heat shock protein 70. Biochem Biophys Res Commun. 459:220–226. 2015. View Article : Google Scholar : PubMed/NCBI

51 

Zhang B, Wu T, Wang Z, Zhang Y, Wang J, Yang B, Zhao Y, Rao Z and Gao J: p38MAPK activation mediates tumor necrosis factor-alpha-induced apoptosis in glioma cells. Mol Med Rep. 11:3101–3107. 2015. View Article : Google Scholar : PubMed/NCBI

52 

Wu KC, Yang ST, Hsia TC, Yang JS, Chiou SM, Lu CC, Wu RS and Chung JG: Suppression of cell invasion and migration by propofol are involved in down-regulating matrix metalloproteinase-2 and p38 MAPK signaling in A549 human lung adenocarcinoma epithelial cells. Anticancer Res. 32:4833–4842. 2012.PubMed/NCBI

53 

Li D, Wang C, Li N and Zhang L: Propofol selectively inhibits nuclear factor-kappaB activity by suppressing p38 mitogen-activated protein kinase signaling in human EA.hy926 endothelial cells during intermittent hypoxia/reoxygenation. Mol Med Rep. 9:1460–1466. 2014. View Article : Google Scholar : PubMed/NCBI

54 

Hsu CP, Lin CH and Kuo CY: Endothelial-cell inflammation and damage by reactive oxygen species are prevented by propofol via ABCA1-mediated cholesterol efflux. Int J Med Sci. 15:978–985. 2018. View Article : Google Scholar : PubMed/NCBI

55 

Chen L, Yang G and Dong H: Everolimus reverses palbociclib resistance in ER+ human breast cancer cells by inhibiting phosphatidylinositol 3-Kinase(PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. Med Sci Monit. 25:77–86. 2019. View Article : Google Scholar : PubMed/NCBI

56 

Barra F, Evangelisti G, Ferro Desideri L, Di Domenico S, Ferraioli D, Vellone VG, De Cian F and Ferrero S: Investigational PI3K/AKT/mTOR inhibitors in development for endometrial cancer. Expert Opin Investig Drugs. 28:131–142. 2019. View Article : Google Scholar : PubMed/NCBI

57 

Hu M, Zhu SX, Xiong SW, Xue XX and Zhou XD: MicroRNAs and the PTEN/PI3K/Akt pathway in gastric cancer (Review). Oncol Rep. 43:1439–1454. 2019.

58 

Hsing CH, Chen YH, Chen CL, Huang WC, Lin MC, Tseng PC, Wang CY, Tsai CC, Choi PC and Lin CF: Anesthetic propofol causes glycogen synthase kinase-3beta-regulated lysosomal/mitochondrial apoptosis in macrophages. Anesthesiology. 116:868–881. 2012. View Article : Google Scholar : PubMed/NCBI

59 

Sun X, Gu J, Chi M, Li M, Lei S and Wang G: Activation of PI3K-Akt through taurine is critical for propofol to protect rat cardiomyocytes from doxorubicin-induced toxicity. Can J Physiol Pharmacol. 92:155–161. 2014. View Article : Google Scholar : PubMed/NCBI

60 

Padmanabhan A, Frangopoulos C and Shaffer LET: Patient satisfaction with propofol for outpatient colonoscopy: A prospective, randomized, double-blind study. Dis Colon Rectum. 60:1102–1108. 2017. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

June 2019
Volume 41 Issue 6

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Kang, F., Wang, S., So, E.C., Chang, M., Wong, K., Cheng, K.S. ... Huang, B. (2019). Propofol may increase caspase and MAPK pathways, and suppress the Akt pathway to induce apoptosis in MA‑10 mouse Leydig tumor cells. Oncology Reports, 41, 3565-3574. https://doi.org/10.3892/or.2019.7129
MLA
Kang, F., Wang, S., So, E. C., Chang, M., Wong, K., Cheng, K. S., Chen, Y., Huang, B."Propofol may increase caspase and MAPK pathways, and suppress the Akt pathway to induce apoptosis in MA‑10 mouse Leydig tumor cells". Oncology Reports 41.6 (2019): 3565-3574.
Chicago
Kang, F., Wang, S., So, E. C., Chang, M., Wong, K., Cheng, K. S., Chen, Y., Huang, B."Propofol may increase caspase and MAPK pathways, and suppress the Akt pathway to induce apoptosis in MA‑10 mouse Leydig tumor cells". Oncology Reports 41, no. 6 (2019): 3565-3574. https://doi.org/10.3892/or.2019.7129