S-Adenosylmethionine enhances the inhibitory effect of gemcitabine against pancreatic cancer cells via suppression of the EGFR/AKT pathways

Molecular & Cellular Toxicology - Tập 18 - Trang 499-508 - 2022
Yan Liu1,2, Linxun Liu1, Yang Zhang1, Lei Qin1
1Department of General Surgery, Hepatobiliary Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China
2Department of General Surgery, Xuzhou Central Hospital Affiliated to Medical School of Southeast University, Xuzhou, China

Tóm tắt

Natural chemical SAM (S-adenosylmethionine) is present in all living cells and plays an important role in biological transmethylation. Recent studies have shown that SAM possesses many pharmacological activities including anti-cancer effects. However, the complex formation of SAM with gemcitabine on pancreatic carcinoma cells, as well as the specific mechanism, remains unknown. Pancreatic cancer cells (PANC-1 and BxPC-3) were treated with SAM and/or gemcitabine and subjected to MTT, combination index, cell apoptosis, cell migration, western blot, and xenograft tumorigenicity assays in this research. The findings revealed that SAM might synergistically improve gemcitabine’s capacity to prevent the development and proliferation of pancreatic cancer cells. By decreasing the EGFR/AKT pathways, SAM in combination with gemcitabine might promote cell death and impede cell migration. Furthermore, pretreatment with IGF-1 (a particular AKT activator) drastically reduced SAM’s pro-apoptotic activity in pancreatic cancer cells, demonstrating the importance of AKT in this mechanism. Furthermore, following treatment with SAM with gemcitabine, tumor volume and weight were considerably decreased in the PANC-1 xenograft mouse model, and immunohistochemical analysis confirmed the down-regulation of p-EGFR and p-AKT in tumor tissues. By suppressing the EGFR/AKT pathways, SAM could synergistically boost the inhibitory impact of gemcitabine on pancreatic cancer cells and might be a promising therapeutic drug for the management of pancreatic cancer.

Tài liệu tham khảo

Aran V, Omerovic J (2019) Current approaches in NSCLC targeting K-RAS and EGFR. Int J Mol Sci 20:5701 Awad MG et al (2020) Graviola leaves extract enhances the anticancer effect of cisplatin on various cancer cell lines. Mol Cell Toxicol 6:385–399 Barreto SG, D’Onise K (2020) Pancreatic cancer in the Australian population: identifying opportunities for intervention. ANZ J Surg 90:2219–2226 Bray F et al (2018) Global cancer statistics 2018: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424 Burris HA 3rd 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 15:2403–2413 Chou TC (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70:440–446 Hackeng WM, Hruban RH, Offerhaus GJ, Brosens LA (2016) Surgical and molecular pathology of pancreatic neoplasms. Diagn Pathol 11:47 He S et al (2020) Triptolide inhibits PDGF-induced proliferation of ASMCs through G0/G1 cell cycle arrest and suppression of the AKT/NF-κB/cyclinD1 signaling pathway. Eur J Pharmacol 867:172811 Ho WJ, Jaffee EM, Zheng L (2020) The tumour microenvironment in pancreatic cancer—clinical challenges and opportunities. Nat Rev Clin Oncol 17:527–540 Jain T, Dudeja V (2021) The war against pancreatic cancer in 2020—advances on all fronts. Nat Rev Gastroenterol Hepatol 18:99–100 Li TW et al (2009) S-adenosylmethionine and methylthioadenosine inhibit cellular FLICE inhibitory protein expression and induce apoptosis in colon cancer cells. Mol Pharmacol 76:192–200 Li Q et al (2017) S-adenosylmethionine attenuates oxidative stress and neuroinflammation induced by amyloid-β through modulation of glutathione metabolism. J Alzheimers Dis 58:549–558 Li Y, Pan J, Gou M (2019) The anti proliferation, cycle arrest and apoptotic inducing activity of peperomin E on prostate cancer PC-3 cell line. Molecules 24:1472 Liu T et al (2018) Mechanisms of MAFG dysregulation in cholestatic liver injury and development of liver cancer. Gastroenterology 155:557–571 Lozano-Rosas MG et al (2020) Diminished S-adenosylmethionine biosynthesis and its metabolism in a model of hepatocellular carcinoma is recuperated by an adenosine derivative. Cancer Biol Ther 21:81–94 Mahmood N et al (2017) Methyl donor S-adenosylmethionine (SAM) supplementation attenuates breast cancer growth, invasion, and metastasis in vivo; therapeutic and chemopreventive applications. Oncotarget 9:5169–5183 Mahmood N et al (2020) S-adenosylmethionine in combination with decitabine shows enhanced anti-cancer effects in repressing breast cancer growth and metastasis. J Cell Mol Med 24:10322–10337 Mitsudomi T, Yatabe Y (2010) Epidermal growth factor receptor in relation to tumor development: EGFR gene and cancer. FEBS J 277:301–308 N’Guessan KF et al (2020) Enhanced efficacy of combination of gemcitabine and phosphatidylserine-targeted nanovesicles against pancreatic cancer. Mol Ther 28:1876–1886 Oettle H et al (2013) Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 310:1473–1481 Parashar S et al (2015) S-adenosylmethionine blocks osteosarcoma cells proliferation and invasion in vitro and tumor metastasis in vivo: therapeutic and diagnostic clinical applications. Cancer Med 4:732–744 Pavliukeviciene B et al (2019) Amyloid β oligomers inhibit growth of human cancer cells. PLoS ONE 14:e0221563 Ren D et al (2020) Metformin activates the STING/IRF3/IFN-β pathway by inhibiting AKT phosphorylation in pancreatic cancer. Am J Cancer Res 10:2851–2864 Saccarello A et al (2020) Oral administration of S-adenosylmethionine (SAMe) and lactobacillus plantarum HEAL9 improves the mild-to-moderate symptoms of depression: a randomized, double-blind, placebo-controlled study. Prim Care Companion CNS Disord 22:19m02578 Takenaka T et al (2019) Effects of gefitinib treatment on cellular uptake of extracellular vesicles in EGFR-mutant non-small cell lung cancer cells. Int J Pharm 572:118762 Tang R et al (2020) The role of ferroptosis regulators in the prognosis, immune activity and gemcitabine resistance of pancreatic cancer. Ann Transl Med 8:1347 Tempero MA (2019) NCCN guidelines updates: pancreatic cancer. J Natl Compr Canc Netw 17:603–605 Tewari D et al (2019) Natural products targeting the PI3K-Akt-mTOR signaling pathway in cancer: a novel therapeutic strategy. Semin Cancer Biol S. https://doi.org/10.1016/j.semcancer.2019.12.008 Tian J et al (2020) N6-methyladenosine mRNA methylation of PIK3CB regulates AKT signalling to promote PTEN-deficient pancreatic cancer progression. Gut 69:2180–2192 Tompkins KD, Thorburn A (2019) Regulation of apoptosis by autophagy to enhance cancer therapy. Yale J Biol Med 92:707–718 Torphy RJ, Fujiwara Y, Schulick RD (2020) Pancreatic cancer treatment: better, but a long way to go. Surg Today 50:1117–1125 Yan L et al (2019a) S-adenosylmethionine affects cell cycle pathways and suppresses proliferation in liver cells. J Cancer 10:4368–4379 Yan X et al (2019b) MicroRNA-21-5p are involved in apoptosis and invasion of fibroblast-like synoviocytes through PTEN/PI3K/AKT signal. Cytotechnology 71:317–328 Zhang S, Wang J, Yao T, Tao M (2020) LncRNA ZFAS1/miR-589 regulates the PTEN/PI3K/AKT signal pathway in the proliferation, invasion and migration of breast cancer cells. Cytotechnology 72:415–425 Zhao et al (2010) Inhibitory effect of S-adenosylmethionine on the growth of human gastric cancer cells in vivo and in vitro. Chin J Cancer 9:752–760 Zhou X et al (2019) TRIM44 is indispensable for glioma cell proliferation and cell cycle progression through AKT/p21/p27 signaling pathway. J Neurooncol 145:211–222