Top

Clinical and Translational Oncology

Published in:

01-07-2020 | Prostate Cancer | Research Article

Cross-talk between ribosome biogenesis, translation, and mTOR in CD133+ 4/CD44+ prostate cancer stem cells

Authors: Z. Binal, E. Açıkgöz, F. Kızılay, G. Öktem, B. Altay

Published in: Clinical and Translational Oncology | Issue 7/2020

Abstract

Objective

To investigate the gene expression profile of CSCs and to explore the key pathways and specific molecular signatures involved in the characteristic of CSCs.

Materials and methods

CD133+ /CD44+ CSCs and bulk population (non-CSCs) were isolated from DU-145 cells using fluorescence-activated cell sorting (FACS). We used Illumina HumanHT-12 v4 Expression to investigate gene expression profiling of CSCs and non-CSCs. Protein–protein interaction (PPI) network analysis was performed using the STRING database. Biomarkers selected based on gene expression profiling were visually analyzed using immunofluorescence staining method. An image analysis program, ImageJ®, was used for the analysis of fluorescence intensity.

Results

In microarray analysis, we found that many ribosomal proteins and translation initiation factors that constitute the mTOR complex were highly expressed. PPI analysis using the 33 genes demonstrated that there was a close interaction between ribosome biogenesis, translation, and mTOR signaling. The fluorescence amount of mTOR and MLST8 were higher in CSCs compared to non-CSCs.

Conclusions

The increase in a number of genes associated with ribosome biogenesis, translation, and mTOR signaling may be important to evaluate prognosis and determine treatment approach for prostate cancer (PCa). A better understanding of the molecular pathways associated with CSCs may be promising to develop targeted therapies to prolong survival in PCa.

Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM. Cancer stem cells–perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res. 2006;66(19):9339–444. https://doi.org/10.1158/0008-5472.CAN-06-3126.CrossRefPubMed

Patrawala L, Calhoun T, Schneider-Broussard R, Li H, Bhatia B, Tang S, Reilly JG, Chandra D, Zhou J, Claypool K, Coghlan L, Tang DG. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene. 2006;25(12):1696–708. https://doi.org/10.1038/sj.onc.1209327.CrossRefPubMed

Hurt EM, Kawasaki BT, Klarmann GJ, Thomas SB, Farrar WL. CD44+ CD24(−) prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis. Br J Cancer. 2008;98(4):756–65. https://doi.org/10.1038/sj.bjc.6604242.CrossRefPubMedPubMedCentral

Klonisch T, Wiechec E, Hombach-Klonisch S, Ande SR, Wesselborg S, Schulze-Osthoff K, Los M. Cancer stem cell markers in common cancers—therapeutic implications. Trends Mol Med. 2008;14(10):450–60. https://doi.org/10.1016/j.molmed.2008.08.003.CrossRefPubMed

Pettersson A, Graff RE, Bauer SR, Pitt MJ, Lis RT, Stack EC, Martin NE, Kunz L, Penney KL, Ligon AH, Suppan C, Flavin R, Sesso HD, Rider JR, Sweeney C, Stampfer MJ, Fiorentino M, Kantoff PW, Sanda MG, Giovannucci EL, Ding EL, Loda M, Mucci LA. The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2012;21(9):1497–509. https://doi.org/10.1158/1055-9965.EPI-12-0042.CrossRefPubMedPubMedCentral

Korsten H, Ziel-van der Made A, Ma X, van der Kwast T, Trapman J. Accumulating progenitor cells in the luminal epithelial cell layer are candidate tumor initiating cells in a Pten knockout mouse prostate cancer model. PLoS ONE. 2009;4(5):e5662. https://doi.org/10.1371/journal.pone.0005662.CrossRefPubMedPubMedCentral

Jiang SJ, Wang S. Dual targeting of mTORC1 and mTORC2 by INK-128 potently inhibits human prostate cancer cell growth in vitro and in vivo. Tumour Biol. 2015;36(10):8177–84. https://doi.org/10.1007/s13277-015-3536-6.CrossRefPubMed

Edlind MP, Hsieh AC. PI3K-AKT-mTOR signaling in prostate cancer progression and androgen deprivation therapy resistance. Asian J Androl. 2014;16(3):378–86. https://doi.org/10.4103/1008-682X.122876.CrossRefPubMedPubMedCentral

Bastide A, David A. The ribosome, (slow) beating heart of cancer (stem) cell. Oncogenesis. 2018;7(4):34. https://doi.org/10.1038/s41389-018-0044-8.CrossRefPubMedPubMedCentral

10.

Guimaraes JC, Zavolan M. Patterns of ribosomal protein expression specify normal and malignant human cells. Genome Biol. 2016;17(1):236. https://doi.org/10.1186/s13059-016-1104-z.CrossRefPubMedPubMedCentral

11.

Hsieh AC, Liu Y, Edlind MP, Ingolia NT, Janes MR, Sher A, Shi EY, Stumpf CR, Christensen C, Bonham MJ, Wang S, Ren P, Martin M, Jessen K, Feldman ME, Weissman JS, Shokat KM, Rommel C, Ruggero D. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature. 2012;485(7396):55–61. https://doi.org/10.1038/nature10912.CrossRefPubMedPubMedCentral

12.

Gentilella A, Kozma SC, Thomas G. A liaison between mTOR signaling, ribosome biogenesis and cancer. Biochimica et Biophysica Acta (BBA) Gene Regulatory Mechanisms. 2015;1849(7):812–20.CrossRef

13.

Lamb R, Harrison H, Smith DL, Townsend PA, Jackson T, Ozsvari B, Martinez-Outschoorn UE, Pestell RG, Howell A, Lisanti MP, Sotgia F. Targeting tumor-initiating cells: eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction. Oncotarget. 2015;6(7):4585–601. https://doi.org/10.18632/oncotarget.3278.CrossRefPubMedPubMedCentral

14.

Kakumoto K, Ikeda J, Okada M, Morii E, Oneyama C. mLST8 promotes mTOR-mediated tumor progression. PLoS ONE. 2015;10(4):e0119015. https://doi.org/10.1371/journal.pone.0119015.CrossRefPubMedPubMedCentral

15.

Slattery ML, Herrick JS, Lundgreen A, Fitzpatrick FA, Curtin K, Wolff RK. Genetic variation in a metabolic signaling pathway and colon and rectal cancer risk: mTOR, PTEN, STK11, RPKAA1, PRKAG2, TSC1, TSC2, PI3K and Akt1. Carcinogenesis. 2010;31(9):1604–11. https://doi.org/10.1093/carcin/bgq142.CrossRefPubMedPubMedCentral

16.

Lin J, Wang J, Greisinger AJ, Grossman HB, Forman MR, Dinney CP, Hawk ET, Wu X. Energy balance, the PI3K-AKT-mTOR pathway genes, and the risk of bladder cancer. Cancer Prev Res (Phila). 2010;3(4):505–17. https://doi.org/10.1158/1940-6207.CAPR-09-0263.CrossRef

17.

Liu Q, Thoreen C, Wang J, Sabatini D, Gray NS. mTOR mediated anti-cancer drug discovery. Drug Discov Today Ther Strateg. 2009;6(2):47–55. https://doi.org/10.1016/j.ddstr.2009.12.001.CrossRefPubMedPubMedCentral

18.

Guertin DA, Sabatini DM. The pharmacology of mTOR inhibition. Sci Signal. 2009;2(67):pe24. https://doi.org/10.1126/scisignal.267pe24.CrossRefPubMed

19.

Oneyama C, Kito Y, Asai R, Ikeda J, Yoshida T, Okuzaki D, Kokuda R, Kakumoto K, Takayama K, Inoue S, Morii E, Okada M. MiR-424/503-mediated Rictor upregulation promotes tumor progression. PLoS ONE. 2013;8(11):e80300. https://doi.org/10.1371/journal.pone.0080300.CrossRefPubMedPubMedCentral

20.

Doghman M, El Wakil A, Cardinaud B, Thomas E, Wang J, Zhao W, Peralta-Del Valle MH, Figueiredo BC, Zambetti GP, Lalli E. Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors. Cancer Res. 2010;70(11):4666–755. https://doi.org/10.1158/0008-5472.CAN-09-3970.CrossRefPubMedPubMedCentral

21.

Nagaraja AK, Creighton CJ, Yu Z, Zhu H, Gunaratne PH, Reid JG, Olokpa E, Itamochi H, Ueno NT, Hawkins SM. A link between mir-100 and FRAP1/mTOR in clear cell ovarian cancer. Mol Endocrinol. 2010;24(2):447–63.CrossRef

22.

Uesugi A, Kozaki K, Tsuruta T, Furuta M, Morita K, Imoto I, Omura K, Inazawa J. The tumor suppressive microRNA miR-218 targets the mTOR component Rictor and inhibits AKT phosphorylation in oral cancer. Cancer Res. 2011;71(17):5765–78. https://doi.org/10.1158/0008-5472.CAN-11-0368.CrossRefPubMed

23.

Liu P, Gan W, Inuzuka H, Lazorchak AS, Gao D, Arojo O, Liu D, Wan L, Zhai B, Yu Y, Yuan M, Kim BM, Shaik S, Menon S, Gygi SP, Lee TH, Asara JM, Manning BD, Blenis J, Su B, Wei W. Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat Cell Biol. 2013;15(11):1340–50. https://doi.org/10.1038/ncb2860.CrossRefPubMedPubMedCentral

24.

Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J, Brown M, Fitzgerald KJ, Sabatini DM. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell. 2006;11(6):859–71. https://doi.org/10.1016/j.devcel.2006.10.007.CrossRefPubMed

25.

Armengol G, Rojo F, Castellví J, Iglesias C, Cuatrecasas M, Pons B, Baselga J, y Cajal SR. 4E-binding protein 1: a key molecular “funnel factor” in human cancer with clinical implications. Can Res. 2007;67(16):7551–5.CrossRef

26.

Frey JW, Jacobs BL, Goodman CA, Hornberger TA. A role for Raptor phosphorylation in the mechanical activation of mTOR signaling. Cell Signal. 2014;26(2):313–22. https://doi.org/10.1016/j.cellsig.2013.11.009.CrossRefPubMed

27.

Guertin DA, Stevens DM, Saitoh M, Kinkel S, Crosby K, Sheen J-H, Mullholland DJ, Magnuson MA, Wu H, Sabatini DM. mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice. Cancer Cell. 2009;15(2):148–59.CrossRef

28.

Martelli AM, Evangelisti C, Follo MY, Ramazzotti G, Fini M, Giardino R, Manzoli L, McCubrey JA, Cocco L. Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling network in cancer stem cells. Curr Med Chem. 2011;18(18):2715–26.CrossRef

29.

Murray NP, Aedo S, Fuentealba C, Reyes E, Jacob O. How localized is pathologically localized prostate cancer? The use of secondary circulating prostate cells as a marker of minimal residual disease and their association with patient outcome. Turkish journal of urology. 2017;43(4):456.CrossRef

30.

Arthurs C, Murtaza BN, Thomson C, Dickens K, Henrique R, Patel HRH, Beltran M, Millar M, Thrasivoulou C, Ahmed A. Expression of ribosomal proteins in normal and cancerous human prostate tissue. PLoS ONE. 2017;12(10):e0186047. https://doi.org/10.1371/journal.pone.0186047.CrossRefPubMedPubMedCentral

31.

Akbayir S, Muslu N, Erden S, Bozlu M. Diagnostic value of microRNAs in prostate cancer patients with prostate specific antigen (PSA) levels between 2, and 10 ng/mL. Turk J Urol. 2016;42(4):247–55. https://doi.org/10.5152/tud.2016.52463.CrossRefPubMedPubMedCentral

32.

Erol A, Acikgoz E, Guven U, Duzagac F, Turkkani A, Colcimen N, Oktem G. Ribosome biogenesis mediates antitumor activity of flavopiridol in CD44(+)/CD24(-) breast cancer stem cells. Oncol Lett. 2017;14(6):6433–40. https://doi.org/10.3892/ol.2017.7029.CrossRefPubMedPubMedCentral

Title: Cross-talk between ribosome biogenesis, translation, and mTOR in CD133+ 4/CD44+ prostate cancer stem cells
Authors: Z. Binal
E. Açıkgöz
F. Kızılay
G. Öktem
B. Altay
Publication date: 01-07-2020
Publisher: Springer International Publishing
Keywords: Prostate Cancer
Prostate Cancer
Published in: Clinical and Translational Oncology / Issue 7/2020
Print ISSN: 1699-048X
Electronic ISSN: 1699-3055
DOI: https://doi.org/10.1007/s12094-019-02229-1

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Objective

Materials and methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 7/2020

HLA-G as a new tumor biomarker: detection of soluble isoforms of HLA-G in the serum and saliva of patients with colorectal cancer

Vitexin, an inhibitor of hypoxia-inducible factor-1α, enhances the radiotherapy sensitization of hyperbaric oxygen on glioma

The prognostic role of FZD6 in esophageal squamous cell carcinoma patients

Situation, challenges, and SEOM recommendations for the future of undergraduate education in Oncology in Spain

Paradoxical prognostic phenomenon of plasma T-cell-derived circulating DNA level in advanced non-small cell lung cancer

Prognostic factors associated with survival in a large cohort of gastric cancer patients resected over a decade at a single Italian center: the Cremona experience

Keynote webinar | Spotlight on antibody–drug conjugates in cancer