nach oben

Cancer Chemotherapy and Pharmacology

Erschienen in:

01.05.2011 | Original Article

Rapamycin suppresses ROS-dependent apoptosis caused by selenomethionine in A549 lung carcinoma cells

verfasst von: Maiko Suzuki, Manabu Endo, Fumiaki Shinohara, Seishi Echigo, Hidemi Rikiishi

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 5/2011

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Although selenium compounds possess chemotherapeutic features by inducing apoptosis in cancer cells with trivial side effects on normal cells, the mechanisms underlying its anti-cancer activity are insufficiently understood at the present. In this study, we investigated the effects of rapamycin on apoptosis induced by seleno-L-methionine (SeMet) or selenite in A549 cells.

Methods

The effects of Se compounds, SeMet and selenite, on cell proliferation, apoptosis and its signaling pathway were investigated in established human adenocarcinoma cell line (A549). Cancer cells were treated with each Se during different periods. Cell apoptosis and signaling molecules were analyzed by flow cytometry (TUNEL method) or immunoblotting, respectively.

Results

SeMet induces reactive oxygen species generation associated with the induction of apoptosis, because pretreatment of cells with N-acetyl-L-cysteine completely blocked SeMet-induced apoptosis. We also found that rapamycin completely suppressed the apoptosis of cells treated by SeMet, but not selenite. SeMet-induced apoptosis is significantly downregulated in combination with PI3 K family inhibitors (LY294002, wortmannin, PI-103, and 3-methyladenine). In addition, ROS generation was included in downstream signaling events associated with the phosphorylation of mTOR, because pretreatment of cells with rapamycin inhibited ROS generation.

Conclusion

These results suggest that SeMet-induced apoptosis is affected by the Akt/mTOR/ROS pathway in A549 cells. Akt serves an anti-survival function in the system of SeMet-treated lung cancer cells, but autophagic signaling remained unsolved.

Rayman MP (2000) The importance of selenium to human health. Lancet 356:233–241PubMedCrossRef

Suzuki M, Endo M, Shinohara F, Echigo S, Rikiishi H (2010) Differential apoptotic response of human cancer cells to organoselenium compounds. Cancer Chemother Pharmacol 66:475–484PubMedCrossRef

Fakih MG, Pendyala L, Brady W, Smith PF, Ross ME, Creaven PJ, Badmaev V, Prey JD, Rustum YM (2008) A Phase I and pharmacokinetic study of selenomethionine in combination with a fixed dose of irinotecan in solid tumors. Cancer Chemother Pharmacol 62:499–508PubMedCrossRef

Schrauzer GN (2000) Selenomethionine: a review of its nutritional significance, metabolism and toxicity. J Nutr 130:1653–1656PubMed

Unni E, Koul D, Yung WK, Sinha R (2005) Se-methylselenocysteine inhibits phosphatidylinositol 3-kinase activity of mouse mammary epithelial tumor cells in Vitro. Breast Cancer Res 7:699–707CrossRef

Hu H, Jiang C, Li G, Lu J (2005) PKB/AKT and ERK regulation of caspase-mediated apoptosis by methylseleninic acid in LNCaP prostate cancer cells. Carcinogenesis 26:1374–1381PubMedCrossRef

Zhao R, Xiang N, Domann FE, Zhong W (2009) Effects of selenite and genistein on G2/M cell cycle arrest and apoptosis in human prostate cancer cells. Nutr Cancer 61:397–407PubMedCrossRef

Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657PubMedCrossRef

Nogueira V, Park Y, Chen CC, Xu PZ, Chen ML, Tonic I, Unterman T, Hay N (2008) Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 14:458–470PubMedCrossRef

10.

Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484PubMedCrossRef

11.

Petroulakis E, Mamane Y, Le Bacquer O, Shahbazian D, Sonenberg N (2006) mTOR signaling: Implications for cancer and anticancer therapy. Br J Cancer 94:195–199PubMedCrossRef

12.

Paglin S, Lee NY, Nakar C, Fitzgerald M, Plotkin J, Deuel B, Hackett N, McMahill M, Sphicas E, Lampen N, Yahalom J (2005) Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells. Cancer Res 65:11061–11070PubMedCrossRef

13.

Mondesire WH, Jian W, Zhang H, Ensor J, Hung MC, Mills GB, Meric-Bernstam F (2004) Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin Cancer Res 10:7031–7042PubMedCrossRef

14.

Hussain SP, Hofseth LJ, Harris CC (2003) Radical causes of cancer. Nat Rev Cancer 3:276–285PubMedCrossRef

15.

Huang P, Feng L, Oldham EA, Keating MJ, Plunkett W (2000) Superoxide dismutase as a target for the selective killing of cancer cells. Nature 407:390–395PubMedCrossRef

16.

Hu D, Liu Q, Cui H, Wang H, Han D, Xu H (2005) Effects of amino acids from selenium-rich silkworm pupas on human hepatoma cells. Life Sci 77:2098–2110PubMedCrossRef

17.

Koshikawa N, Hayashi J, Nakagawara A, Takenaga K (2009) Reactive oxygen species-generating mitochondrial DNA mutation up-regulates hypoxia-inducible factor-1α gene transcription via phosphatidylinositol 3-kinase-Akt/protein kinase C/histone deacetylase pathway. J Biol Chem 284:33185–33194PubMedCrossRef

18.

Suzuki M, Shinohara F, Rikiishi H (2008) Zebularine-induced reduction in VEGF secretion by HIF-1α degradation in oral squamous cell carcinoma. Mol Med Rep 1:465–471

19.

Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi Y, Yoshimori T (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 21:5720–5728CrossRef

20.

Maynard S, Schurman SH, Harboe C, de Souza-Pinto NC, Bohr VA (2009) Base excision repair of oxidative DNA damage and association with cancer and aging. Carcinogenesis 30:2–10PubMedCrossRef

21.

Huang F, Nie C, Yang Y, Yue W, Ren Y, Shang Y, Wang X, Jin H, Xu C, Chen Q (2009) Selenite induces redox-dependent Bax activation and apoptosis in colorectal cancer cells. Free Radic Biol Med 46:1186–1196PubMedCrossRef

22.

Chen T, Wong YS (2009) Selenocystine induces reactive oxygen species-mediated apoptosis in human cancer cells. Biomed Pharmacother 63:105–113PubMedCrossRef

23.

Kim JH, Chu SC, Gramlich JL, Pride YB, Babendreier E, Chauhan D, Salgia R, Podar K, Griffin JD, Sattler M (2005) Activation of the PI3 K/mTOR pathway by BCR-ABL contributes to increased production of reactive oxygen species. Blood 105:1717–1723PubMedCrossRef

24.

Maddika S, Ande SR, Wiechec E, Hansen LL, Wesselborg S, Los M (2008) Akt-mediated phosphorylation of CDK2 regulates its dual role in cell cycle progression and apoptosis. J Cell Sci 121:979–988PubMedCrossRef

25.

Lu B, Wang L, Stehlik C, Medan D, Huang C, Hu S, Chen F, Shi X, Rojanasakul Y (2006) Phosphatidylinositol 3-kinase/Akt positively regulates Fas (CD95)-mediated apoptosis in epidermal Cl41 cells. J Immunol 176:6785–6793PubMed

26.

Van Gorp AG, Pomeranz KM, Birkenkamp KU, Hui RC, Lam EW, Coffer PJ (2006) Chronic protein kinase B (PKB/c-akt) activation leads to apoptosis induced by oxidative stress-mediated Foxo3a transcriptional up-regulation. Cancer Res 66:10760–10769PubMedCrossRef

27.

Ren Y, Huang F, Liu Y, Yang Y, Jiang Q, Xu C (2009) Autophagy inhibition through PI3 K/Akt increases apoptosis by sodium selenite in NB4 cells. BMB Rep 42:599–604PubMed

28.

Honeggar M, Beck R, Moos PJ (2009) Thioredoxin reductase 1 ablation sensitizes colon cancer cells to methylseleninate-mediated cytotoxicity. Toxicol Appl Pharmacol 241:348–355PubMedCrossRef

29.

Carloni S, Girelli S, Scopa C, Buonocore G, Longini M, Balduini W (2010) Activation of autophagy and Akt/CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia-ischemia. Autophagy 6:366–377PubMedCrossRef

30.

Shi Y, Yan H, Frost P, Gera J, Lichtenstein A (2005) Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol Cancer Ther 4:1533–1540PubMedCrossRef

31.

Matsuzaki T, Yashiro M, Kaizaki R, Yasuda K, Doi Y, Sawada T, Ohira M, Hirakawa K (2009) Synergistic antiproliferative effect of mTOR inhibitors in combination with 5-fluorouracil in scirrhous gastric cancer. Cancer Sci 100:2402–2410PubMedCrossRef

32.

Workman P, Clarke PA, Raynaud FI, van Montfort RL (2010) Drugging the PI3 kinome: from chemical tools to drugs in the clinic. Cancer Res 70:2146–2157PubMedCrossRef

33.

Ito S, Koshikawa N, Mochizuki S, Takenaga K (2007) 3-Methyladenine suppresses cell migration and invasion of HT1080 fibrosarcoma cells through inhibiting phosphoinositide 3-kinases independently of autophagy inhibition. Int J Oncol 31:261–268PubMed

Titel: Rapamycin suppresses ROS-dependent apoptosis caused by selenomethionine in A549 lung carcinoma cells
verfasst von: Maiko Suzuki
Manabu Endo
Fumiaki Shinohara
Seishi Echigo
Hidemi Rikiishi
Publikationsdatum: 01.05.2011
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 5/2011
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-010-1417-7

Springer Medizin

Rapamycin suppresses ROS-dependent apoptosis caused by selenomethionine in A549 lung carcinoma cells

Abstract

Purpose

Methods

Results

Conclusion

Neu im Fachgebiet Onkologie

Alphablocker schützt vor Miktionsproblemen nach der Biopsie

Mammakarzinom: Senken Statine das krebsbedingte Sterberisiko?

Labor, CT-Anthropometrie zeigen Risiko für Pankreaskrebs

Viel pflanzliche Nahrung, seltener Prostata-Ca.-Progression

Update Onkologie

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusion

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 5/2011

A combined pharmacokinetic model for the hypoxia-targeted prodrug PR-104A in humans, dogs, rats and mice predicts species differences in clearance and toxicity

H1, a novel derivative of tetrandrine reverse P-glycoprotein-mediated multidrug resistance by inhibiting transport function and expression of P-glycoprotein

A phase II, randomized, multicenter study to assess the efficacy, safety, and tolerability of zibotentan (ZD4054) in combination with pemetrexed in patients with advanced non-small cell lung cancer

Erratum to: Reductive metabolism of the dinitrobenzamide mustard anticancer prodrug PR-104 in mice

Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs

Sunitinib improves chemotherapeutic efficacy and ameliorates cisplatin-induced nephrotoxicity in experimental animals

Neu im Fachgebiet Onkologie

Alphablocker schützt vor Miktionsproblemen nach der Biopsie

Mammakarzinom: Senken Statine das krebsbedingte Sterberisiko?

Labor, CT-Anthropometrie zeigen Risiko für Pankreaskrebs

Viel pflanzliche Nahrung, seltener Prostata-Ca.-Progression

Update Onkologie