pp32 (ANP32A) expression inhibits pancreatic cancer cell growth and induces gemcitabine resistance by disrupting HuR binding to mRNAs

Timothy K. Williams, Christina L. Costantino, Nikolai A. Bildzukewicz, Nathan G. Richards, David W. Rittenhouse, Lisa Einstein, Joseph A. Cozzitorto, Judith C. Keen, Abhijit Dasgupta, Myriam Gorospe, Gregory E. Gonye, Charles J. Yeo, Agnieszka K. Witkiewicz, Jonathan R. Brody

Research output: Contribution to journalArticle

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Abstract

The expression of protein phosphatase 32 (PP32, ANP32A) is low in poorly differentiated pancreatic cancers and is linked to the levels of HuR (ELAV1), a predictive marker for gemcitabine response. In pancreatic cancer cells, exogenous overexpression of pp32 inhibited cell growth, supporting its long-recognized role as a tumor suppressor in pancreatic cancer. In chemotherapeutic sensitivity screening assays, cells overexpressing pp32 were selectively resistant to the nucleoside analogs gemcitabine and cytarabine (ARA-C), but were sensitized to 5-fluorouracil; conversely, silencing pp32 in pancreatic cancer cells enhanced gemcitabine sensitivity. The cytoplasmic levels of pp32 increased after cancer cells are treated with certain stressors, including gemcitabine. pp32 overexpression reduced the association of HuR with the Mrna encoding the gemcitabine-metabolizing enzyme deoxycytidine kinase (dCK), causing a significant reduction in dCK protein levels. Similarly, ectopic pp32 expression caused a reduction in HuR binding of mRNAs encoding tumor-promoting proteins (e.g., VEGF and HuR), while silencing pp32 dramatically enhanced the binding of these mRNA targets. Low pp32 nuclear expression correlated with high-grade tumors and the presence of lymph node metastasis, as compared to patients' tumors with high nuclear pp32 expression. Although pp32 expression levels did not enhance the predictive power of cytoplasmic HuR status, nuclear pp32 levels and cytoplasmic HuR levels associated significantly in patient samples. Thus, we provide novel evidence that the tumor suppressor function of pp32 can be attributed to its ability to disrupt HuR binding to target mRNAs encoding key proteins for cancer cell survival and drug efficacy.

Original languageEnglish (US)
Article numbere15455
JournalPLoS One
Volume5
Issue number11
DOIs
StatePublished - 2010

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gemcitabine
pancreatic neoplasms
Cell growth
Pancreatic Neoplasms
Tumors
cell growth
Messenger RNA
neoplasms
Deoxycytidine Kinase
Cells
Growth
Neoplasms
fluorouracil
Proteins
nucleosides
Phosphoprotein Phosphatases
Cytarabine
Nucleosides
Fluorouracil
metastasis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Williams, T. K., Costantino, C. L., Bildzukewicz, N. A., Richards, N. G., Rittenhouse, D. W., Einstein, L., ... Brody, J. R. (2010). pp32 (ANP32A) expression inhibits pancreatic cancer cell growth and induces gemcitabine resistance by disrupting HuR binding to mRNAs. PLoS One, 5(11), [e15455]. https://doi.org/10.1371/journal.pone.0015455

pp32 (ANP32A) expression inhibits pancreatic cancer cell growth and induces gemcitabine resistance by disrupting HuR binding to mRNAs. / Williams, Timothy K.; Costantino, Christina L.; Bildzukewicz, Nikolai A.; Richards, Nathan G.; Rittenhouse, David W.; Einstein, Lisa; Cozzitorto, Joseph A.; Keen, Judith C.; Dasgupta, Abhijit; Gorospe, Myriam; Gonye, Gregory E.; Yeo, Charles J.; Witkiewicz, Agnieszka K.; Brody, Jonathan R.

In: PLoS One, Vol. 5, No. 11, e15455, 2010.

Research output: Contribution to journalArticle

Williams, TK, Costantino, CL, Bildzukewicz, NA, Richards, NG, Rittenhouse, DW, Einstein, L, Cozzitorto, JA, Keen, JC, Dasgupta, A, Gorospe, M, Gonye, GE, Yeo, CJ, Witkiewicz, AK & Brody, JR 2010, 'pp32 (ANP32A) expression inhibits pancreatic cancer cell growth and induces gemcitabine resistance by disrupting HuR binding to mRNAs', PLoS One, vol. 5, no. 11, e15455. https://doi.org/10.1371/journal.pone.0015455
Williams, Timothy K. ; Costantino, Christina L. ; Bildzukewicz, Nikolai A. ; Richards, Nathan G. ; Rittenhouse, David W. ; Einstein, Lisa ; Cozzitorto, Joseph A. ; Keen, Judith C. ; Dasgupta, Abhijit ; Gorospe, Myriam ; Gonye, Gregory E. ; Yeo, Charles J. ; Witkiewicz, Agnieszka K. ; Brody, Jonathan R. / pp32 (ANP32A) expression inhibits pancreatic cancer cell growth and induces gemcitabine resistance by disrupting HuR binding to mRNAs. In: PLoS One. 2010 ; Vol. 5, No. 11.
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abstract = "The expression of protein phosphatase 32 (PP32, ANP32A) is low in poorly differentiated pancreatic cancers and is linked to the levels of HuR (ELAV1), a predictive marker for gemcitabine response. In pancreatic cancer cells, exogenous overexpression of pp32 inhibited cell growth, supporting its long-recognized role as a tumor suppressor in pancreatic cancer. In chemotherapeutic sensitivity screening assays, cells overexpressing pp32 were selectively resistant to the nucleoside analogs gemcitabine and cytarabine (ARA-C), but were sensitized to 5-fluorouracil; conversely, silencing pp32 in pancreatic cancer cells enhanced gemcitabine sensitivity. The cytoplasmic levels of pp32 increased after cancer cells are treated with certain stressors, including gemcitabine. pp32 overexpression reduced the association of HuR with the Mrna encoding the gemcitabine-metabolizing enzyme deoxycytidine kinase (dCK), causing a significant reduction in dCK protein levels. Similarly, ectopic pp32 expression caused a reduction in HuR binding of mRNAs encoding tumor-promoting proteins (e.g., VEGF and HuR), while silencing pp32 dramatically enhanced the binding of these mRNA targets. Low pp32 nuclear expression correlated with high-grade tumors and the presence of lymph node metastasis, as compared to patients' tumors with high nuclear pp32 expression. Although pp32 expression levels did not enhance the predictive power of cytoplasmic HuR status, nuclear pp32 levels and cytoplasmic HuR levels associated significantly in patient samples. Thus, we provide novel evidence that the tumor suppressor function of pp32 can be attributed to its ability to disrupt HuR binding to target mRNAs encoding key proteins for cancer cell survival and drug efficacy.",
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T1 - pp32 (ANP32A) expression inhibits pancreatic cancer cell growth and induces gemcitabine resistance by disrupting HuR binding to mRNAs

AU - Williams, Timothy K.

AU - Costantino, Christina L.

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AU - Richards, Nathan G.

AU - Rittenhouse, David W.

AU - Einstein, Lisa

AU - Cozzitorto, Joseph A.

AU - Keen, Judith C.

AU - Dasgupta, Abhijit

AU - Gorospe, Myriam

AU - Gonye, Gregory E.

AU - Yeo, Charles J.

AU - Witkiewicz, Agnieszka K.

AU - Brody, Jonathan R.

PY - 2010

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N2 - The expression of protein phosphatase 32 (PP32, ANP32A) is low in poorly differentiated pancreatic cancers and is linked to the levels of HuR (ELAV1), a predictive marker for gemcitabine response. In pancreatic cancer cells, exogenous overexpression of pp32 inhibited cell growth, supporting its long-recognized role as a tumor suppressor in pancreatic cancer. In chemotherapeutic sensitivity screening assays, cells overexpressing pp32 were selectively resistant to the nucleoside analogs gemcitabine and cytarabine (ARA-C), but were sensitized to 5-fluorouracil; conversely, silencing pp32 in pancreatic cancer cells enhanced gemcitabine sensitivity. The cytoplasmic levels of pp32 increased after cancer cells are treated with certain stressors, including gemcitabine. pp32 overexpression reduced the association of HuR with the Mrna encoding the gemcitabine-metabolizing enzyme deoxycytidine kinase (dCK), causing a significant reduction in dCK protein levels. Similarly, ectopic pp32 expression caused a reduction in HuR binding of mRNAs encoding tumor-promoting proteins (e.g., VEGF and HuR), while silencing pp32 dramatically enhanced the binding of these mRNA targets. Low pp32 nuclear expression correlated with high-grade tumors and the presence of lymph node metastasis, as compared to patients' tumors with high nuclear pp32 expression. Although pp32 expression levels did not enhance the predictive power of cytoplasmic HuR status, nuclear pp32 levels and cytoplasmic HuR levels associated significantly in patient samples. Thus, we provide novel evidence that the tumor suppressor function of pp32 can be attributed to its ability to disrupt HuR binding to target mRNAs encoding key proteins for cancer cell survival and drug efficacy.

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