Impairment of glioma stem cell survival and growth by a novel inhibitor for survivin-ran protein complex

Hacer Guvenc, Marat S. Pavlyukov, Kaushal Joshi, Habibe Kurt, Yeshavanth K. Banasavadi-Siddegowda, Ping Mao, Christopher Hong, Ryosuke Yamada, Chang Hyuk Kwon, Deepak Bhasin, Somsundaram Chettiar, Gaspar Kitange, In Hee Park, Jann N Sarkaria, Chenglong Li, Mihail I. Shakhparonov, Ichiro Nakano

Research output: Contribution to journalArticle

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Abstract

Purpose: Glioblastoma multiforme (GBM) is a devastating disease. Recent studies suggest that the stem cell properties of GBM contribute to the development of therapy resistance. Experimental Design: The expression of Survivin and Ran was evaluated by immunohistochemistry with GBM tissues, and quantitative reverse transcriptase (qRT)-PCR and immunocytochemistry with patient-derived GBM sphere cultures. With a computational structure-based drug design, 11 small-molecule compounds were designed, synthesized, and evaluated as inhibitor candidates for the molecular interaction of Survivin protein. The molecular mechanism of the lead compound, LLP-3, was determined by Western blot, ELISA, in situ proximity ligation assay, and immunocytochemistry. The effects of LLP-3 treatment on GSCs were evaluated both in vitro and in vivo. Quantitative immunohistochemistry was carried out to compare Survivin expression in tissues from 44 newly diagnosed and 31 recurrent post-chemoradiation GBM patients. Lastly, the sensitivities of temozolomide-resistant GBM spheres to LLP-3 were evaluated in vitro. Results: Survivin and Ran were strongly expressed in GBM tissues, particularly in the perivasculature, and also in patient-derived GSC cultures. LLP-3 treatment disrupted the Survivin-Ran protein complex in cancer cells and abolished the growth of patient-derived GBM spheres in vitro and in vivo. This inhibition was dependent on caspase activity and associated with p53 status of cells. Immunohistochemistry showed that Survivin expression is significantly increased in recurrent GBM compared with newly diagnosed tumors, and temozolomide-resistant GBM spheres exhibited high sensitivities to LLP-3 treatment. Conclusions: Disruption of the Survivin-Ran complex by LLP-3 abolishes survival and growth of GSCs both in vitro and in vivo, indicating an attractive novel therapeutic approach for GBM.

Original languageEnglish (US)
Pages (from-to)631-642
Number of pages12
JournalClinical Cancer Research
Volume19
Issue number3
DOIs
StatePublished - Feb 1 2013

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ran GTP-Binding Protein
Glioblastoma
Glioma
Cell Survival
Stem Cells
Growth
temozolomide
Immunohistochemistry
Therapeutics
Drug Design
Caspases
Reverse Transcriptase Polymerase Chain Reaction
Ligation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Guvenc, H., Pavlyukov, M. S., Joshi, K., Kurt, H., Banasavadi-Siddegowda, Y. K., Mao, P., ... Nakano, I. (2013). Impairment of glioma stem cell survival and growth by a novel inhibitor for survivin-ran protein complex. Clinical Cancer Research, 19(3), 631-642. https://doi.org/10.1158/1078-0432.CCR-12-0647

Impairment of glioma stem cell survival and growth by a novel inhibitor for survivin-ran protein complex. / Guvenc, Hacer; Pavlyukov, Marat S.; Joshi, Kaushal; Kurt, Habibe; Banasavadi-Siddegowda, Yeshavanth K.; Mao, Ping; Hong, Christopher; Yamada, Ryosuke; Kwon, Chang Hyuk; Bhasin, Deepak; Chettiar, Somsundaram; Kitange, Gaspar; Park, In Hee; Sarkaria, Jann N; Li, Chenglong; Shakhparonov, Mihail I.; Nakano, Ichiro.

In: Clinical Cancer Research, Vol. 19, No. 3, 01.02.2013, p. 631-642.

Research output: Contribution to journalArticle

Guvenc, H, Pavlyukov, MS, Joshi, K, Kurt, H, Banasavadi-Siddegowda, YK, Mao, P, Hong, C, Yamada, R, Kwon, CH, Bhasin, D, Chettiar, S, Kitange, G, Park, IH, Sarkaria, JN, Li, C, Shakhparonov, MI & Nakano, I 2013, 'Impairment of glioma stem cell survival and growth by a novel inhibitor for survivin-ran protein complex', Clinical Cancer Research, vol. 19, no. 3, pp. 631-642. https://doi.org/10.1158/1078-0432.CCR-12-0647
Guvenc, Hacer ; Pavlyukov, Marat S. ; Joshi, Kaushal ; Kurt, Habibe ; Banasavadi-Siddegowda, Yeshavanth K. ; Mao, Ping ; Hong, Christopher ; Yamada, Ryosuke ; Kwon, Chang Hyuk ; Bhasin, Deepak ; Chettiar, Somsundaram ; Kitange, Gaspar ; Park, In Hee ; Sarkaria, Jann N ; Li, Chenglong ; Shakhparonov, Mihail I. ; Nakano, Ichiro. / Impairment of glioma stem cell survival and growth by a novel inhibitor for survivin-ran protein complex. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 3. pp. 631-642.
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AU - Kurt, Habibe

AU - Banasavadi-Siddegowda, Yeshavanth K.

AU - Mao, Ping

AU - Hong, Christopher

AU - Yamada, Ryosuke

AU - Kwon, Chang Hyuk

AU - Bhasin, Deepak

AU - Chettiar, Somsundaram

AU - Kitange, Gaspar

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N2 - Purpose: Glioblastoma multiforme (GBM) is a devastating disease. Recent studies suggest that the stem cell properties of GBM contribute to the development of therapy resistance. Experimental Design: The expression of Survivin and Ran was evaluated by immunohistochemistry with GBM tissues, and quantitative reverse transcriptase (qRT)-PCR and immunocytochemistry with patient-derived GBM sphere cultures. With a computational structure-based drug design, 11 small-molecule compounds were designed, synthesized, and evaluated as inhibitor candidates for the molecular interaction of Survivin protein. The molecular mechanism of the lead compound, LLP-3, was determined by Western blot, ELISA, in situ proximity ligation assay, and immunocytochemistry. The effects of LLP-3 treatment on GSCs were evaluated both in vitro and in vivo. Quantitative immunohistochemistry was carried out to compare Survivin expression in tissues from 44 newly diagnosed and 31 recurrent post-chemoradiation GBM patients. Lastly, the sensitivities of temozolomide-resistant GBM spheres to LLP-3 were evaluated in vitro. Results: Survivin and Ran were strongly expressed in GBM tissues, particularly in the perivasculature, and also in patient-derived GSC cultures. LLP-3 treatment disrupted the Survivin-Ran protein complex in cancer cells and abolished the growth of patient-derived GBM spheres in vitro and in vivo. This inhibition was dependent on caspase activity and associated with p53 status of cells. Immunohistochemistry showed that Survivin expression is significantly increased in recurrent GBM compared with newly diagnosed tumors, and temozolomide-resistant GBM spheres exhibited high sensitivities to LLP-3 treatment. Conclusions: Disruption of the Survivin-Ran complex by LLP-3 abolishes survival and growth of GSCs both in vitro and in vivo, indicating an attractive novel therapeutic approach for GBM.

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