Secretory leukocyte protease inhibitor antagonizes paclitaxel in ovarian cancer cells.
OBJECTIVE
Ovarian cancer recurrence with the development of paclitaxel resistance is an obstacle to long-term survival. We showed that secretory leukocyte protease inhibitor (SLPI) is a survival factor for ovarian cancer. We hypothesize that SLPI may antagonize paclitaxel injury.


METHODS
Differential SLPI induction in response to paclitaxel and in response to stable forced expression of SLPI was shown in A2780-1A9 cells and their paclitaxel-resistant sublines, PTX10 and PTX22, and confirmed with HEY-A8 cells. SLPI-mediated survival was reduced by the MAP/extracellular signal-regulated kinase (ERK) kinase inhibitor, U0126, and a humanized neutralizing monoclonal anti-SLPI antibody, CR012. OVCAR3 xenographs tested the role of CR012 in vivo.


RESULTS
SLPI expression was lower in A2780-1A9 ovarian cancer cells than in PTX10 and PTX22, and SLPI was induced by paclitaxel exposure. Stable SLPI expression yielded a proliferation advantage (P = 0.01); expression of and response to SLPI in OVCAR3 cells were abrogated by exposure to CR012. SLPI reduced the paclitaxel susceptibility of 1A9 and HEY-A8 cells (P <or= 0.05), and SLPI expression did not increase the resistance of PTX10 and PTX22 cells. Both paclitaxel and SLPI overexpression induced ERK activation. Inhibition of MAP/ERK kinase with U0126 increased paclitaxel injury and overcame SLPI-mediated cell protection. It did not reinstate PTX10 sensitivity to paclitaxel, which was associated with AKT activation. Significant inhibition of OVCAR3 xenograft growth was observed with CR012 and paclitaxel, over single agents (P <or= 0.001).


CONCLUSIONS
A two-pronged approach confirmed that SLPI overcomes paclitaxel in part through activation of ERK1/2. These results credential SLPI as a molecular target for ovarian cancer and suggest CR012 as a tool for proof of concept.
Rasool
Nabila
N
Molecular Signaling Section, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
LaRochelle
William
W
Zhong
Haihong
H
Ara
Gulshan
G
Cohen
Joshua
J
Kohn
Elise C
EC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004336:Drug Antagonism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D017239:Paclitaxel / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D053481:Secretory Leukocyte Peptidase Inhibitor; D017239:Paclitaxel