Nuclear versus cytoplasmic localization of filamin a in prostate cancer: Immunohistochemical correlation with metastases

Roble G. Bedolla, Yu Wang, Alfredo Asuncion, Karim Chamie, Salma Siddiqui, Maria M. Mudryj, Thomas J. Prihoda, Javed Siddiqui, Arul M. Chinnaiyan, Rohit Mehra, Ralph W. De Vere White, Paramita M. Ghosh

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86 Scopus citations

Abstract

Purpose: We previously showed that nuclear localization of the actin-binding protein, filamin A (Fln A), corresponded to hormone-dependence in prostate cancer. Intact Fln A (280 k Da, cytoplasmic) cleaved to a 90 k Da fragment which translocated to the nucleus in hormone-naïve cells, whereas in hormone-refractory cells, Fln A was phosphorylated, preventing its cleavage and nuclear translocation. We have examined whether Fln A localization determines a propensity to metastasis in advanced androgen-independent prostate cancer. Experimental Design: We examined, by immunohistochemistry, Fln A localization in paraffin-embedded human prostate tissue representing different stages of progression. Results were correlated with in vitro studies in a cell model of prostate cancer. Results: Nuclear Fln A was significantly higher in benign prostate (0.6612 ± 0.5888), prostatic intraepithelial neoplasia (PIN; 0.6024 ± 0.4620), and clinically localized cancers (0.69134 ± 0.5686) compared with metastatic prostate cancers (0.3719 ± 0.4992, P = 0.0007). Cytoplasmic Fln A increased from benign prostate (0.0833 ± 0.2677), PIN (0.1409 ± 0.2293), localized cancers (0.3008 ± 0.3762, P = 0.0150), to metastases (0.7632 ± 0.4414, P < 0.00001). Logistic regression of metastatic versus nonmetastatic tissue yielded the area under the receiver operating curve as 0.67 for nuclear-Fln A, 0.79 for cytoplasmic-Fln A, and 0.82 for both, indicating that metastasis correlates with cytoplasmic to nuclear translocation. In vitro studies showed that cytoplasmic localization of Fln A induced cell invasion whereas nuclear translocation of the protein inhibited it. Fln dephosphorylation with the protein kinase A inhibitor H-89 facilitated Fln A nuclear translocation, resulting in decreased invasiveness and AR transcriptional activity, and induced sensitivity to androgen withdrawal in hormone-refractory cells. Conclusions: The data presented in this study indicate that in prostate cancer, metastasis correlates with cytoplasmic localization of Fln A and may be prevented by cleavage and subsequent nuclear translocation of this protein.

Original languageEnglish (US)
Pages (from-to)788-796
Number of pages9
JournalClinical Cancer Research
Volume15
Issue number3
DOIs
StatePublished - Feb 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Bedolla, R. G., Wang, Y., Asuncion, A., Chamie, K., Siddiqui, S., Mudryj, M. M., Prihoda, T. J., Siddiqui, J., Chinnaiyan, A. M., Mehra, R., De Vere White, R. W., & Ghosh, P. M. (2009). Nuclear versus cytoplasmic localization of filamin a in prostate cancer: Immunohistochemical correlation with metastases. Clinical Cancer Research, 15(3), 788-796. https://doi.org/10.1158/1078-0432.CCR-08-1402