Ectopic NGAL expression can alter sensitivity of breast cancer cells to EGFR, Bcl-2, CaM-K inhibitors and the natural plant product berberine

William H. Chappell, Stephen L. Abrams, Richard A. Franklin, Michelle M. LaHair, Giuseppe Montalto, Melchiorre Cervello, Alberto M. Martelli, Ferdinando Nicoletti, Saverio Candido, Massimo Libra, Jerry Polesel, Renato Talamini, Michele Milella, Agostino Tafuri, Linda S. Steelman, James A. McCubrey

Research output: Contribution to journalArticlepeer-review


Neutrophil gelatinase-associated lipocalin (NGAL, a.k.a Lnc2) is a member of the lipocalin family and has diverse roles. NGAL can stabilize matrix metalloproteinase-9 from autodegradation. NGAL is considered as a siderocalin that is important in the transport of iron. NGAL expression has also been associated with certain neoplasias and is implicated in the metastasis of breast cancer. In a previous study, we examined whether ectopic NGAL expression would alter the sensitivity of breast epithelial, breast and colorectal cancer cells to the effects of the chemotherapeutic drug doxorubicin. While abundant NGAL expression was detected in all the cells infected with a retrovirus encoding NGAL, this expression did not alter the sensitivity of these cells to doxorubicin as compared with empty vector-transduced cells. We were also interested in determining the effects of ectopic NGAL expression on the sensitivity to small-molecule inhibitors targeting key signaling molecules. Ectopic NGAL expression increased the sensitivity of MCF-7 breast cancer cells to EGFR, Bcl2 and calmodulin kinase inhibitors as well as the natural plant product berberine. Furthermore, when suboptimal concentrations of certain inhibitors were combined with doxorubicin, a reduction in the doxorubicin IC50 was frequently observed. An exception was observed when doxorubicin was combined with rapamycin, as doxorubicin suppressed the sensitivity of the NGAL-transduced MCF-7 cells to rapamycin when compared with the empty vector controls. In contrast, changes in the sensitivities of the NGAL-transduced HT-29 colorectal cancer cell line and the breast epithelial MCF-10A cell line were not detected compared with empty vector-transduced cells. Doxorubicin-resistant MCF-7/DoxR cells were examined in these experiments as a control drug-resistant line; it displayed increased sensitivity to EGFR and Bcl-2 inhibitors compared with empty vector transduced MCF-7 cells. These results indicate that NGAL expression can alter the sensitivity of certain cancer cells to small-molecule inhibitors, suggesting that patients whose tumors exhibit elevated NGAL expression or have become drug-resistant may display altered responses to certain small-molecule inhibitors.

Original languageEnglish
Pages (from-to)4447-4461
Number of pages15
JournalCell Cycle
Issue number23
Publication statusPublished - Dec 1 2012


  • BCL-2
  • Berberine
  • Breast cancer
  • Calmodulin kinase
  • Colorectal cancer
  • EGFR
  • Inhibitor sensitivity
  • Lcn2
  • Lipocalins
  • NGAL
  • Rapamycin
  • Siderocalins
  • Targeted therapy

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology


Dive into the research topics of 'Ectopic NGAL expression can alter sensitivity of breast cancer cells to EGFR, Bcl-2, CaM-K inhibitors and the natural plant product berberine'. Together they form a unique fingerprint.

Cite this