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Inhibition of Survival Pathways MAPK and NF-kB Triggers Apoptosis in Pancreatic Ductal Adenocarcinoma Cells via Suppression of Autophagy

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Abstract

Background

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a survival rate of 4–6 months from diagnosis. PDAC is the fourth leading cause of cancer-related death in the Western world, with a mortality rate of 10 cases per 100,000 population. Chemotherapy constitutes only a palliative strategy, with limited effects on life expectancy.

Aims

To investigate the biological response of PDAC to mitogen-activated protein kinase (MAPK) and NF-kappaB (NF-kB) inhibitors and the role of autophagy in the modulation of these signaling pathways in order to address the challenge of developing improved medical protocols for patients with PDAC.

Methods

Two ATCC cell lines, MIAPaCa-2 and PANC-1, were used as PDAC models. Cells were exposed to inhibitors of MAPK or NF-kB survival pathways alone or after autophagy inhibition. Several aspects were analyzed, as follows: cell proliferation, by [3H]TdR incorporation; cell death, by TUNEL assay, regulation of autophagy by LC3-II expression level and modulation of pro-and anti-apoptotic proteins by Western blot.

Results

We demonstrated that the inhibition of the MAPK and NF-kB survival pathways with U0126 and caffeic acid phenethyl ester (CAPE), respectively, produced strong inhibition of pancreatic tumor cell growth without inducing apoptotic death. Interestingly, U0126 and CAPE induced apoptosis after autophagy inhibition in a caspase-dependent manner in MIA PaCa-2 cells and in a caspase-independent manner in PANC-1 cells.

Conclusions

Here we present evidence that allows us to consider a combined therapy regimen comprising an autophagy inhibitor and a MAPK or NF-kB pathway inhibitor as a possible treatment strategy for pancreatic cancer.

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Acknowledgments

The authors thank Dr. Daniela Ureta (Servicio de Citometría de flujo, Departamento de Microbiología, Inmunología y Biotecnología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina) for technical assistance and Martín Levermann for language assistance during the edition of the manuscript.

Compliance with Ethical Standards

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Funding

This study was funded by Universidad de Buenos Aires and Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET).

Conflict of Interest

The authors (DLP, SLL, TS, SC, CYM, VC, EA) declared no conflict of interest.

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Authors and Affiliations

  1. Cátedra de Inmunología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, 4° piso, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina

    Daniela Laura Papademetrio, Silvina Laura Lompardía, Tania Simunovich, Susana Costantino, Cintia Yamila Mihalez, Victoria Cavaliere & Élida Álvarez

  2. IDEHU, CONICET, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina

    Daniela Laura Papademetrio, Silvina Laura Lompardía, Susana Costantino, Cintia Yamila Mihalez & Élida Álvarez

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  1. Daniela Laura Papademetrio
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  2. Silvina Laura Lompardía
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  3. Tania Simunovich
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  4. Susana Costantino
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  5. Cintia Yamila Mihalez
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  6. Victoria Cavaliere
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Correspondence to Daniela Laura Papademetrio or Élida Álvarez.

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Papademetrio, D.L., Lompardía, S.L., Simunovich, T. et al. Inhibition of Survival Pathways MAPK and NF-kB Triggers Apoptosis in Pancreatic Ductal Adenocarcinoma Cells via Suppression of Autophagy. Targ Oncol 11, 183–195 (2016). https://doi.org/10.1007/s11523-015-0388-3

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