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01.02.2014 | Original Article

Antitumor effects of BI-D1870 on human oral squamous cell carcinoma

verfasst von: Chang-Fang Chiu, Li-Yuan Bai, Naval Kapuriya, Shih-Yuan Peng, Chia-Yung Wu, Aaron M. Sargeant, Michael Yuanchien Chen, Jing-Ru Weng

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2014

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Abstract

Purpose

Among the signaling pathways implicated in the tumorigenesis of oral squamous cell carcinoma (OSCC) is the extracellular signal-regulated kinase mitogen-activated protein kinase pathway, a downstream target of which is a family of serine/threonine kinases known as the 90 kDa ribosomal S6 kinases (RSKs). This study aims to investigate the role of BI-D1870, a specific inhibitor of p90 RSKs, in a panel of OSCC cell lines.

Methods

The antitumor effects and mechanisms of BI-D1870 were assessed by MTT assays, flow cytometry, Western blotting, transfection, and confocal microscopy.

Results

BI-D1870 exhibited a dose-responsive antiproliferative effect on OSCC cells with relative sparing of normal human oral keratinocytes. The compound inhibited the downstream RSK target YB-1 and caused apoptosis as evidenced by PARP cleavage, activation of the caspase cascade, and the presence of pyknotic nuclei in the 4,6-diamidino-2-phenylindole assay. In addition, BI-D1870 also induced G2/M arrest by modulating the expression of p21 and other cell cycle regulators. Other newly discovered anticancer attributes of BI-D1870 included the generation of reactive oxygen species and increases in endoplasmic reticulum stress and autophagy.

Conclusions

Together, these results suggest the translational value of BI-D1870 in oral squamous cell carcinoma therapy.

Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, Stewart JS, Jelic S, Betka J, Preiss JH, van den Weyngaert D, Awada A, Cupissol D, Kienzer HR, Rey A, Desaunois I, Bernier J, Lefebvre JL (2007) Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 357:1695–1704PubMedCrossRef

Anjum R, Blenis J (2008) The RSK family of kinases: emerging roles in cellular signalling. Nat Rev Mol Cell Biol 9:747–758PubMedCrossRef

Frodin M, Gammeltoft S (1999) Role and regulation of 90 kDa ribosomal S6 kinase (RSK) in signal transduction. Mol Cell Endocrinol 151:65–77PubMedCrossRef

Chen RH, Sarnecki C, Blenis J (1992) Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol Cell Biol 12:915–927PubMedCentralPubMed

Kang S, Elf S, Lythgoe K, Hitosugi T, Taunton J, Zhou W, Xiong L, Wang D, Muller S, Fan S, Sun SY, Marcus AI, Gu TL, Polakiewicz RD, Chen ZG, Khuri FR, Shin DM, Chen J (2010) p90 ribosomal S6 kinase 2 promotes invasion and metastasis of human head and neck squamous cell carcinoma cells. J Clin Invest 120:1165–1177PubMedCentralPubMedCrossRef

Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, McLauchlan H, Klevernic I, Arthur JS, Alessi DR, Cohen P (2007) The selectivity of protein kinase inhibitors: a further update. Biochem J 408:297–315PubMedCrossRef

Sapkota GP, Cummings L, Newell FS, Armstrong C, Bain J, Frodin M, Grauert M, Hoffmann M, Schnapp G, Steegmaier M, Cohen P, Alessi DR (2007) BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo. Biochem J 401:29–38PubMedCrossRef

Nguyen TL (2008) Targeting RSK: an overview of small molecule inhibitors. Anticancer Agents Med Chem 8:710–716PubMedCrossRef

Chambard JC, Lefloch R, Pouyssegur J, Lenormand P (2007) ERK implication in cell cycle regulation. Biochim Biophys Acta 1773:1299–1310PubMedCrossRef

10.

Stratford AL, Fry CJ, Desilets C, Davies AH, Cho YY, Li Y, Dong Z, Berquin IM, Roux PP, Dunn SE (2008) Y-box binding protein-1 serine 102 is a downstream target of p90 ribosomal S6 kinase in basal-like breast cancer cells. Breast Cancer Res 10:R99PubMedCentralPubMedCrossRef

11.

Fang J, Seki T, Maeda H (2009) Therapeutic strategies by modulating oxygen stress in cancer and inflammation. Adv Drug Deliv Rev 61:290–302PubMedCrossRef

12.

Kim I, Xu W, Reed JC (2008) Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 7:1013–1030PubMedCrossRef

13.

Lin Y, Wang Z, Liu L, Chen L (2011) Akt is the downstream target of GRP78 in mediating cisplatin resistance in ER stress-tolerant human lung cancer cells. Lung Cancer 71:291–297PubMedCrossRef

14.

Mathew R, Karantza-Wadsworth V, White E (2007) Role of autophagy in cancer. Nat Rev Cancer 7:961–967PubMedCentralPubMedCrossRef

15.

Scherz-Shouval R, Elazar Z (2011) Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 36:30–38PubMedCrossRef

16.

Tanimura S, Hashizume J, Kurosaki Y, Sei K, Gotoh A, Ohtake R, Kawano M, Watanabe K, Kohno M (2011) SH3P2 is a negative regulator of cell motility whose function is inhibited by ribosomal S6 kinase-mediated phosphorylation. Genes Cells 16:514–526PubMedCrossRef

17.

Petrella BL, Armstrong DA, Vincenti MP (2011) CCAAT-enhancer-binding protein beta activation of MMP-1 gene expression in SW1353 cells: independent roles of extracellular signal-regulated and p90/ribosomal S6 kinases. J Cell Physiol 226:3349–3354PubMedCrossRef

18.

Chen S, Mackintosh C (2009) Differential regulation of NHE1 phosphorylation and glucose uptake by inhibitors of the ERK pathway and p90RSK in 3T3-L1 adipocytes. Cell Signal 21:1984–1993PubMedCrossRef

19.

Mishima K, Yamada E, Masui K, Shimokawara T, Takayama K, Sugimura M, Ichijima K (1998) Overexpression of the ERK/MAP kinases in oral squamous cell carcinoma. Mod Pathol 11:886–891PubMed

20.

Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298:1911–1912PubMedCrossRef

21.

McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, Stivala F, Libra M, Basecke J, Evangelisti C, Martelli AM, Franklin RA (2007) Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 1773:1263–1284PubMedCentralPubMedCrossRef

22.

Das N, Majumder J, DasGupta UB (2000) ras gene mutations in oral cancer in eastern India. Oral Oncol 36:76–80PubMedCrossRef

23.

Chang SE, Bhatia P, Johnson NW, Morgan PR, McCormick F, Young B, Hiorns L (1991) Ras mutations in United Kingdom examples of oral malignancies are infrequent. Int J Cancer 48:409–412PubMedCrossRef

24.

Mishima K, Inoue K, Hayashi Y (2002) Overexpression of extracellular-signal regulated kinases on oral squamous cell carcinoma. Oral Oncol 38:468–474PubMedCrossRef

25.

Partridge M, Gullick WJ, Langdon JD, Sherriff M (1988) Expression of epidermal growth factor receptor on oral squamous cell carcinoma. Br J Oral Maxillofac Surg 26:381–389PubMedCrossRef

26.

Werkmeister R, Brandt B, Joos U (2000) Clinical relevance of erbB-1 and -2 oncogenes in oral carcinomas. Oral Oncol 36:100–105PubMedCrossRef

27.

Yu T, Wu Y, Helman JI, Wen Y, Wang C, Li L (2011) CXCR4 promotes oral squamous cell carcinoma migration and invasion through inducing expression of MMP-9 and MMP-13 via the ERK signaling pathway. Mol Cancer Res 9:161–172PubMedCrossRef

28.

Yang LC, Yang SH, Tai KW, Chou MY, Yang JJ (2004) MEK inhibition enhances bleomycin A5-induced apoptosis in an oral cancer cell line: signaling mechanisms and therapeutic opportunities. J Oral Pathol Med 33:37–45PubMedCrossRef

29.

Hu P, Han Z, Couvillon AD, Exton JH (2004) Critical role of endogenous Akt/IAPs and MEK1/ERK pathways in counteracting endoplasmic reticulum stress-induced cell death. J Biol Chem 279:49420–49429PubMedCrossRef

30.

Zhang LJ, Chen S, Wu P, Hu CS, Thorne RF, Luo CM, Hersey P, Zhang XD (2009) Inhibition of MEK blocks GRP78 up-regulation and enhances apoptosis induced by ER stress in gastric cancer cells. Cancer Lett 274:40–46PubMedCrossRef

Titel: Antitumor effects of BI-D1870 on human oral squamous cell carcinoma
verfasst von: Chang-Fang Chiu
Li-Yuan Bai
Naval Kapuriya
Shih-Yuan Peng
Chia-Yung Wu
Aaron M. Sargeant
Michael Yuanchien Chen
Jing-Ru Weng
Publikationsdatum: 01.02.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2014
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-013-2349-9

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Antitumor effects of BI-D1870 on human oral squamous cell carcinoma