Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma

Jinhee Kim, Eric Jonasch, Angela Alexander, John D. Short, Shengli Cai, Sijin Wen, Dimitra Tsavachidou, Pheroze Tamboli, Bogdan A. Czerniak, Kim Anh Do, Kevin J. Wu, Laura A. Marlow, Christopher G. Wood, John A III Copland, Cheryl Lyn Walker

Research output: Contribution to journalArticle

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Abstract

Purpose: p27 localization and expression has prognostic and predictive value in cancer. Little is known regarding expression patterns of p27 in renal cell carcinoma (RCC) or how p27 participates in disease progression or response to therapy. Experimental Design: RCC-derived cell lines, primary tumors, and normal renal epithelial cells were analyzed for p27 expression, phosphorylation (T157 of the NLS), and subcellular localization. RCC-derived cell lines were treated with phosphatidylinositol 3-kinase (PI3K)and mammalian target of rapamycin (mTOR) inhibitors and effects on p27 localization were assessed. The potential contribution of cytoplasmic p27 to resistance to apoptosis was also evaluated. Results: p27 was elevated in tumors compared with matched controls, and cytoplasmic mislocalization of p27 was associated with increasing tumor grade. Cytoplasmic localization of p27 correlated with phosphorylation at T157, an AKT phosphorylation site in the p27 NLS. In RCC cell lines, activated PI3K/AKT signaling was accompanied by mislocalization of p27. AKT activation and phosphorylation of p27 was associated with resistance to apoptosis, and small interfering RNA knockdown of p27 or relocalization to the nucleus increased apoptosis in RCC cells. Treatment with the PI3K inhibitors LY294002 or wortmannin resulted in nuclear relocalization of p27, whereas mTOR inhibition by rapamycin did not. Conclusions: In RCC, p27 is phosphorylated at T157 of the NLS, with increasing tumor grade associated with cytoplasmic p27. PI3K inhibition (which reduces AKT activity) reduces T157 phosphorylation and induces nuclear relocalization of p27, whereas mTOR inhibition does not. Clinical testing of these findings may provide a rational approach for use of mTOR and PI3K/AKT pathway inhibitors in patients with RCC.

Original languageEnglish (US)
Pages (from-to)81-90
Number of pages10
JournalClinical Cancer Research
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2009

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Phosphatidylinositol 3-Kinase
Renal Cell Carcinoma
Sirolimus
Phosphorylation
Apoptosis
Neoplasms
Cell Line
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Tumor Cell Line
Small Interfering RNA
Disease Progression
Research Design
Epithelial Cells
Kidney
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Kim, J., Jonasch, E., Alexander, A., Short, J. D., Cai, S., Wen, S., ... Walker, C. L. (2009). Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma. Clinical Cancer Research, 15(1), 81-90. https://doi.org/10.1158/1078-0432.CCR-08-0170

Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma. / Kim, Jinhee; Jonasch, Eric; Alexander, Angela; Short, John D.; Cai, Shengli; Wen, Sijin; Tsavachidou, Dimitra; Tamboli, Pheroze; Czerniak, Bogdan A.; Do, Kim Anh; Wu, Kevin J.; Marlow, Laura A.; Wood, Christopher G.; Copland, John A III; Walker, Cheryl Lyn.

In: Clinical Cancer Research, Vol. 15, No. 1, 01.01.2009, p. 81-90.

Research output: Contribution to journalArticle

Kim, J, Jonasch, E, Alexander, A, Short, JD, Cai, S, Wen, S, Tsavachidou, D, Tamboli, P, Czerniak, BA, Do, KA, Wu, KJ, Marlow, LA, Wood, CG, Copland, JAIII & Walker, CL 2009, 'Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma', Clinical Cancer Research, vol. 15, no. 1, pp. 81-90. https://doi.org/10.1158/1078-0432.CCR-08-0170
Kim, Jinhee ; Jonasch, Eric ; Alexander, Angela ; Short, John D. ; Cai, Shengli ; Wen, Sijin ; Tsavachidou, Dimitra ; Tamboli, Pheroze ; Czerniak, Bogdan A. ; Do, Kim Anh ; Wu, Kevin J. ; Marlow, Laura A. ; Wood, Christopher G. ; Copland, John A III ; Walker, Cheryl Lyn. / Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 1. pp. 81-90.
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abstract = "Purpose: p27 localization and expression has prognostic and predictive value in cancer. Little is known regarding expression patterns of p27 in renal cell carcinoma (RCC) or how p27 participates in disease progression or response to therapy. Experimental Design: RCC-derived cell lines, primary tumors, and normal renal epithelial cells were analyzed for p27 expression, phosphorylation (T157 of the NLS), and subcellular localization. RCC-derived cell lines were treated with phosphatidylinositol 3-kinase (PI3K)and mammalian target of rapamycin (mTOR) inhibitors and effects on p27 localization were assessed. The potential contribution of cytoplasmic p27 to resistance to apoptosis was also evaluated. Results: p27 was elevated in tumors compared with matched controls, and cytoplasmic mislocalization of p27 was associated with increasing tumor grade. Cytoplasmic localization of p27 correlated with phosphorylation at T157, an AKT phosphorylation site in the p27 NLS. In RCC cell lines, activated PI3K/AKT signaling was accompanied by mislocalization of p27. AKT activation and phosphorylation of p27 was associated with resistance to apoptosis, and small interfering RNA knockdown of p27 or relocalization to the nucleus increased apoptosis in RCC cells. Treatment with the PI3K inhibitors LY294002 or wortmannin resulted in nuclear relocalization of p27, whereas mTOR inhibition by rapamycin did not. Conclusions: In RCC, p27 is phosphorylated at T157 of the NLS, with increasing tumor grade associated with cytoplasmic p27. PI3K inhibition (which reduces AKT activity) reduces T157 phosphorylation and induces nuclear relocalization of p27, whereas mTOR inhibition does not. Clinical testing of these findings may provide a rational approach for use of mTOR and PI3K/AKT pathway inhibitors in patients with RCC.",
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T1 - Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma

AU - Kim, Jinhee

AU - Jonasch, Eric

AU - Alexander, Angela

AU - Short, John D.

AU - Cai, Shengli

AU - Wen, Sijin

AU - Tsavachidou, Dimitra

AU - Tamboli, Pheroze

AU - Czerniak, Bogdan A.

AU - Do, Kim Anh

AU - Wu, Kevin J.

AU - Marlow, Laura A.

AU - Wood, Christopher G.

AU - Copland, John A III

AU - Walker, Cheryl Lyn

PY - 2009/1/1

Y1 - 2009/1/1

N2 - Purpose: p27 localization and expression has prognostic and predictive value in cancer. Little is known regarding expression patterns of p27 in renal cell carcinoma (RCC) or how p27 participates in disease progression or response to therapy. Experimental Design: RCC-derived cell lines, primary tumors, and normal renal epithelial cells were analyzed for p27 expression, phosphorylation (T157 of the NLS), and subcellular localization. RCC-derived cell lines were treated with phosphatidylinositol 3-kinase (PI3K)and mammalian target of rapamycin (mTOR) inhibitors and effects on p27 localization were assessed. The potential contribution of cytoplasmic p27 to resistance to apoptosis was also evaluated. Results: p27 was elevated in tumors compared with matched controls, and cytoplasmic mislocalization of p27 was associated with increasing tumor grade. Cytoplasmic localization of p27 correlated with phosphorylation at T157, an AKT phosphorylation site in the p27 NLS. In RCC cell lines, activated PI3K/AKT signaling was accompanied by mislocalization of p27. AKT activation and phosphorylation of p27 was associated with resistance to apoptosis, and small interfering RNA knockdown of p27 or relocalization to the nucleus increased apoptosis in RCC cells. Treatment with the PI3K inhibitors LY294002 or wortmannin resulted in nuclear relocalization of p27, whereas mTOR inhibition by rapamycin did not. Conclusions: In RCC, p27 is phosphorylated at T157 of the NLS, with increasing tumor grade associated with cytoplasmic p27. PI3K inhibition (which reduces AKT activity) reduces T157 phosphorylation and induces nuclear relocalization of p27, whereas mTOR inhibition does not. Clinical testing of these findings may provide a rational approach for use of mTOR and PI3K/AKT pathway inhibitors in patients with RCC.

AB - Purpose: p27 localization and expression has prognostic and predictive value in cancer. Little is known regarding expression patterns of p27 in renal cell carcinoma (RCC) or how p27 participates in disease progression or response to therapy. Experimental Design: RCC-derived cell lines, primary tumors, and normal renal epithelial cells were analyzed for p27 expression, phosphorylation (T157 of the NLS), and subcellular localization. RCC-derived cell lines were treated with phosphatidylinositol 3-kinase (PI3K)and mammalian target of rapamycin (mTOR) inhibitors and effects on p27 localization were assessed. The potential contribution of cytoplasmic p27 to resistance to apoptosis was also evaluated. Results: p27 was elevated in tumors compared with matched controls, and cytoplasmic mislocalization of p27 was associated with increasing tumor grade. Cytoplasmic localization of p27 correlated with phosphorylation at T157, an AKT phosphorylation site in the p27 NLS. In RCC cell lines, activated PI3K/AKT signaling was accompanied by mislocalization of p27. AKT activation and phosphorylation of p27 was associated with resistance to apoptosis, and small interfering RNA knockdown of p27 or relocalization to the nucleus increased apoptosis in RCC cells. Treatment with the PI3K inhibitors LY294002 or wortmannin resulted in nuclear relocalization of p27, whereas mTOR inhibition by rapamycin did not. Conclusions: In RCC, p27 is phosphorylated at T157 of the NLS, with increasing tumor grade associated with cytoplasmic p27. PI3K inhibition (which reduces AKT activity) reduces T157 phosphorylation and induces nuclear relocalization of p27, whereas mTOR inhibition does not. Clinical testing of these findings may provide a rational approach for use of mTOR and PI3K/AKT pathway inhibitors in patients with RCC.

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