Oncotarget

Research Papers:

Leptin-Notch axis impairs 5-fluorouracil effects on pancreatic cancer

Adriana Harbuzariu and Ruben Rene Gonzalez-Perez _

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Oncotarget. 2018; 9:18239-18253. https://doi.org/10.18632/oncotarget.24435

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Abstract

Adriana Harbuzariu1 and Ruben Rene Gonzalez-Perez1

1Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA

Correspondence to:

Ruben Rene Gonzalez-Perez, email: [email protected]

Keywords: 5-Fluorouracil; pancreatic cancer; leptin; Notch; cytotoxicity

Received: December 19, 2017    Accepted: January 30, 2018    Published: April 06, 2018

ABSTRACT

5-FU chemotherapy is a current strategy to treat pancreatic cancer (PC), but unfortunately chemoresistance is eventually developed in most patients. Obesity is a risk factor for PC that could affect 5-FU effectiveness through the adipokine leptin, which is a known proliferation, survival factor and Notch inducer. We investigated whether leptin signaling affects 5-FU cytotoxicity on PC. To this end, tumorspheres developed from BxPC-3 and MiaPaCa-2 PC cells were treated with 5-FU, leptin, inhibitors for Notch (DAPT) and leptin signaling (IONP-LPrA2) and ATP-binding cassette of proteins (Probenecid). Leptin treatment decreased 5-FU cytotoxicity, and increased cell proliferation, colony forming ability, stem cell, pluripotency, EMT markers, drug efflux proteins (ABCC5, ABCC11) and Notch. In addition, leptin reduced the 5-FU effects on apoptosis by decreasing pro-apoptotic (Bax, Caspase-3 activation and PARP degradation) and increasing anti-apoptotic factors (RIP and Bcl-XL). Leptin’s effects on PC tumorspheres treated with 5-FU were reduced by IONP-LPrA2 and were mainly Notch signaling- dependent and more evident in MiaPaCa-2-derived tumorspheres. Present results suggest that leptin could impair 5-FU cytotoxicity and promote chemoresistance. Therefore, targeting the leptin-Notch axis could be a novel way to improve 5-FU therapy for PC patients, especially in obesity context.


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