Advertisement

S-Adenosylmethionine synergistically enhances the antitumor effect of gemcitabine against pancreatic cancer through JAK2/STAT3 pathway

  • Yan Liu
  • Tingting Bi
  • Linxun Liu
  • Quangen Gao
  • Genhai ShenEmail author
  • Lei QinEmail author
Original Article
  • 92 Downloads

Abstract

Gemcitabine (GEM) has been widely used for pancreatic cancer (PC) treatment but limited by the development of drug resistance. The agents that reverse its resistance and improve the chemo-sensitivity are urgently needed. S-Adenosylmethionine (SAM) is a precursor for polyamine biosynthesis in mammalian cells and plays a key role in biological transmethylation events. It is reported that SAM could be used as a therapeutic reagent for cancer treatments. In this study, we investigated the chemo-sensitization of SAM to potentiate the antitumor effect of GEM in PC. After treating PC cells with GEM and/or SAM, different subsequent experiments were performed. Results showed that SAM plus GEM could significantly inhibit the growth and proliferation of PC cells, and SAM acts synergistically with GEM. The combinative treatment could induce cell apoptosis and inhibit invasion and migration through JAK2/STAT3 inactivation. Inhibition of JAK2/STAT3 pathway significantly enhanced the pro-apoptotic effect of SAM, suggesting the key roles of JAK2/STAT3 in the process. Moreover, co-treatment with GEM and SAM exhibited more efficient inhibition of tumor weight and volume on PANC-1 xenograft mouse model compared to GEM or SAM alone and has no significant effect on the function of the liver and kidney. In general, this study indicated that SAM synergistically enhanced the antitumor effect of GEM against PC through suppressed JAK2/STAT3 pathway, and SAM is applicable as a promising agent to improve the sensitivity of PC to GEM.

Keywords

S-Adenosylmethionine Pancreatic cancer Gemcitabine Synergistically JAK2/STAT3 

Notes

Author contribution statement

LY, QL, and SGH carried out the main work and drafted the manuscript. BTT and LLX carried out the western blot and immunohistochemistry. LY and BTT carried out the in vivo study. LY and GQG performed the statistical analysis. QL and LY designed the study. All authors read and approved the final manuscript.

Funding information

The present study was supported by the Program for Medical and health application basic research of Suzhou City (No.SYSD2016042), the Program for Wujiang No.1 People’s Hospital (No.201603).

Compliance with ethical standards

All experiments were approved by the Wujiang No.1 People’s Hospital Ethics Committee.

Conflict of interest

The authors declare that they have no competing interests.

References

  1. Bottiglieri T (2002) S-Adenosyl-L-methionine (SAMe): from the bench to the bedside—molecular basis of a pleiotrophic molecule. Am J Clin Nutr 76:1151S–1157SCrossRefGoogle Scholar
  2. Burris HA III, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413CrossRefGoogle Scholar
  3. Chou TC (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70:440–446CrossRefGoogle Scholar
  4. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M, Groupe Tumeurs Digestives of Unicancer, PRODIGE Intergroup (2011) Digestives of Unicancer, and PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817–1825CrossRefGoogle Scholar
  5. Ediriwickrema A, Zhou J, Deng Y, Saltzman WM (2014) Multilayered nanoparticles for combination gene and drug delivery to tumors. Biomaterials 35:9343–9354CrossRefGoogle Scholar
  6. Gong J, Tuli R, Shinde A, Hendifar AE (2015) Meta-analyses of treatment standards for pancreatic cancer. Mol Clin Oncol 716:315–325Google Scholar
  7. Grasso C, Jansen G, Giovannetti E (2017) Drug resistance in pancreatic cancer: impact of altered energy metabolism. Crit Rev Oncol Hematol 114:139–152CrossRefGoogle Scholar
  8. Jorvig JE, Chakraborty A (2015) Zerumbone inhibits growth of hormone refractory prostate cancer cells by inhibiting JAK2/STAT3 pathway and increases paclitaxel sensitivity. Anti-Cancer Drugs 26:160–166CrossRefGoogle Scholar
  9. Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV et al (2016) Pancreatic cancer. Nat Rev Dis Primers 04:16022CrossRefGoogle Scholar
  10. Li D, Xie K, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet 363:1049–1057CrossRefGoogle Scholar
  11. Li TW, Zhang Q, Oh P, Xia M, Chen H, Bemanian S et al (2009) S-Adenosylmethionine and methylthioadenosine inhibit cellular FLICE inhibitory protein expression and induce apoptosis in colon cancer cells. Mol Pharmacol 76:192–200CrossRefGoogle Scholar
  12. Liu J, Yao Y, Ding H, Chen R (2014) Oxymatrine triggers apoptosis y regulating Bcl-2 family proteins and activating caspase-3/caspase-9 pathway in human leukemia HL-60 cells. Tumour Biol 35:5409–5415CrossRefGoogle Scholar
  13. Liu Y, Bi T, Wang G, Dai W, Wu G, Qian L, Gao Q, Shen G (2015) Lupeol inhibits proliferation and induces apoptosis of human pancreatic cancer PCNA-1 cells through AKT/ERK pathways. Naunyn Schmiedeberg's Arch Pharmacol 388:295–304CrossRefGoogle Scholar
  14. Liu X, Ji Q, Ye N, Sui H, Zhou L, Zhu H, Fan Z, Cai J, Li Q (2015a) Berberine inhibits invasion and metastasis of colorectal cancer cells via COX-2/PGE2 mediated JAK2/STAT3 signaling pathway. PLoS One 10:e0123478CrossRefGoogle Scholar
  15. Liu Y, Bi T, Shen G, Li Z, Wu G, Wang Z, Qian L, Gao Q (2016) Lupeol induces apoptosis and inhibits invasion in gallbladder carcinoma GBC-SD cells by suppression of EGFR/MMP-9 signaling pathway. Cytotechnology 68:123–133CrossRefGoogle Scholar
  16. Liu Y, Bi T, Dai W, Wang G, Qian L, Gao Q, Shen G (2016a) Oxymatrine synergistically enhances the inhibitory effect of 5-fluorouracil on hepatocellular carcinoma in vitro and in vivo. Tumour Biol 37:7589–7597CrossRefGoogle Scholar
  17. Lu SC, Mato JM (2005) Role of methionine adenosyltransferase and Sadenosylmethionine in alcohol-associated liver cancer. Alcohol 35:227–234CrossRefGoogle Scholar
  18. Ma D, Shen B, Seewoo V, Tong H, Yang W, Cheng C et al (2016) GADD45β induction by S-adenosylmethionine inhibits hepatocellular carcinoma cell proliferation during acute ischemia-hypoxia. Oncotarget 14:37215–37225Google Scholar
  19. Mahmood N, Cheishvili D, Arakelian A, Tanvir I, Khan HA, Pépin AS, Szyf M, Rabbani SA (2018) Methyl donor S-adenosylmethionine (SAM) supplementation attenuates breast cancer growth, invasion, and metastasis in vivo; therapeutic and chemopreventive applications. Oncotarget 9:5169–5183CrossRefGoogle Scholar
  20. Ouyang J, Pan X, Lin H, Hu Z, Xiao P, Hu H (2017) GKN2 increases apoptosis, reduces the proliferation and invasion ability of gastric cancer cells through down-regulating the JAK/STAT signaling pathway. Am J Transl Res 9:803e811Google Scholar
  21. Parashar S, Cheishvili D, Arakelian A, Hussain Z, Tanvir I, Khan HA, Szyf M, Rabbani SA (2015) S-Adenosylmethionine blocks osteosarcoma cells proliferation and invasion in vitro and tumor metastasis in vivo: therapeutic and diagnostic clinical applications. Cancer Med 4:732–744CrossRefGoogle Scholar
  22. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74:2913–2921CrossRefGoogle Scholar
  23. Rajasinghe LD, Pindiprolu RH, Gupta SV (2018) Delta-tocotrienol inhibits non-small-cell lung cancer cell invasion via the inhibition of nF-κB, uPa activator, and MMP-9. Onco Targets Ther 11:4301–4314CrossRefGoogle Scholar
  24. Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67:7–30CrossRefGoogle Scholar
  25. Simpson CD, Anyiwe K, Schimmer AD (2008) Anoikis resistance and tumor metastasis. Cancer Lett 272:177–185CrossRefGoogle Scholar
  26. Stathis A, Moor MJ (2010) Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol 7:163–172CrossRefGoogle Scholar
  27. Tota R, Pauf JM, Berlin JD (2014) Treatment of metastatic pancreatic adenocarcinoma: a review. Oncology 28:70–74Google Scholar
  28. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M et al (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691–7703CrossRefGoogle Scholar
  29. Wu KJ, Huang JM, Zhong HJ, Dong ZZ, Vellaisamy K, Lu JJ, Chen XP, Chiu P, Kwong DWJ, Han QB, Ma DL, Leung CH (2017) A natural product-like JAK2/STAT3 inhibitor induces apoptosis of malignant melanoma cells. PLoS One 12:e0177123CrossRefGoogle Scholar
  30. Xin H, Herrmann A, Reckamp K, Zhang W, Pal S, Hedvat M, Zhang C, Liang W, Scuto A, Weng S, Morosini D, Cao ZA, Zinda M, Figlin R, Huszar D, Jove R, Yu H (2011) Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480. Cancer Res 71:6601–6610CrossRefGoogle Scholar
  31. Yu C, Chen S, Guo Y, Sun C (2018) Oncogenic TRIM31 confers gemcitabine resistance in pancreatic cancer via activating the NF-κB signaling pathway. Theranostics 8:3224–3236CrossRefGoogle Scholar
  32. Zhao M, Gao FH, Wang JY, Liu F, Yuan HH, Zhang WY, Jiang B (2011) JAK2/ STAT3 signaling pathway activation mediates tumor angiogenesis by upregulation of VEGF and bFGF in non-small-cell lung cancer. Lung Cancer 73:366–374CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of General Surgery, Hepatobiliary surgeryThe First Affiliated Hospital of Soochow UniversitySuzhouChina
  2. 2.Department of General Surgeryaffiliated Wujiang Hospital of Nantong UniversitySuzhouChina
  3. 3.Department of Geriatric Wardaffiliated Wujiang Hospital of Nantong UniversitySuzhouChina

Personalised recommendations