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

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 isimportant in the transport of iron. NGAL expression has also been associated with certain neoplasias and is implicatedin the metastasis of breast cancer. In a previous study, we examined whether ectopic NGAL expression would alter thesensitivity 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 expressiondid not alter the sensitivity of these cells to doxorubicin as compared with empty vector-transduced cells. We were alsointerested in determining the effects of ectopic NGAL expression on the sensitivity to small-molecule inhibitors targetingkey signaling molecules. Ectopic NGAL expression increased the sensitivity of MCF-7 breast cancer cells to EGFR, Bcl2and calmodulin kinase inhibitors as well as the natural plant product berberine. Furthermore, when suboptimalconcentrations of certain inhibitors were combined with doxorubicin, a reduction in the doxorubicin IC50 was frequentlyobserved. An exception was observed when doxorubicin was combined with rapamycin, as doxorubicin suppressed thesensitivity 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-10Acell line were not detected compared with empty vector-transduced cells. Doxorubicin-resistant MCF-7/DoxR cells wereexamined in these experiments as a control drug-resistant line; it displayed increased sensitivity to EGFR and Bcl-2inhibitors compared with empty vector transduced MCF-7 cells. These results indicate that NGAL expression can alter thesensitivity of certain cancer cells to small-molecule inhibitors, suggesting that patients whose tumors exhibit elevatedNGAL expression or have become drug-resistant may display altered responses to certain small-molecule inhibitors.