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Interplay between autophagy and apoptosis in pancreatic tumors in response to gemcitabine

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Abstract

Pancreatic cancer is an aggressive disease. Its incidence has increased over the last two decades. It is currently the fourth cause of death among cancers in the western world. Unfortunately, systemic chemotherapy still relies on just a few drugs which until now have produced unsatisfactory results. Gemcitabine (2′-2′-difluorodeoxycytidine) is currently the standard chemotherapy treatment at all stages of pancreatic adenocarcinoma. Survival benefit and clinical impact however remain moderate due to a high degree of intrinsic and acquired resistance. Autophagy plays an important role in cell death decision but can also protect cells from various apoptotic stimuli. We investigated the function of autophagy in pancreatic carcinoma cells, which are frequently insensitive to standard chemotherapeutic agents. Here, we demonstrate that autophagy is one of the mechanisms responsible for the refractory response of pancreatic tumors to gemcitabine. We present evidence in vitro and in vivo that proves autophagy plays a protective role in pancreatic ductal carcinoma cells, preventing them from entering the apoptotic pathway after stimulus with gemcitabine, thus contributing to treatment resistance. A better understanding of the role in the process may help in the discovery of new strategies to overcome tumor drug resistance in this aggressive disease.

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Conflict of interest

The authors declare no conflict of interest

Grant support

This study was supported by grants from Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) PIP no. 0199 and Secretaría de Ciencia y Tecnología Universidad de Buenos Aires B011 and 20020100100185.

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Authors and Affiliations

  1. IDEHU-CONICET, 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, Victoria Cavaliere, Tania Simunovich, Susana Costantino, María Dolores Campos, Tomás Lombardo & Élida Álvarez

  2. Laboratorio de Biología Celular y Molecular, IHEM-CONICET, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Mendoza, Argentina

    Claudio Marcelo Fader Kaiser

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  1. Daniela Laura Papademetrio
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  2. Victoria Cavaliere
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  3. Tania Simunovich
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  4. Susana Costantino
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  5. María Dolores Campos
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  6. Tomás Lombardo
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  7. Claudio Marcelo Fader Kaiser
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  8. Élida Álvarez
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Correspondence to Daniela Laura Papademetrio.

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Papademetrio, D.L., Cavaliere, V., Simunovich, T. et al. Interplay between autophagy and apoptosis in pancreatic tumors in response to gemcitabine. Targ Oncol 9, 123–134 (2014). https://doi.org/10.1007/s11523-013-0278-5

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