Targeting of NAD metabolism in pancreatic cancer cells

Potential novel therapy for pancreatic tumors AC

Claudia C S Chini, Anatilde M. Gonzalez Guerrico, Veronica Nin, Juliana Camacho-Pereira, Carlos Escande, Maria Thereza Barbosa, Eduardo Nunes Chini

Research output: Contribution to journalArticle

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Abstract

Purpose: Here, we describe a novel interplay between NAD synthesis and degradation involved in pancreatic tumor growth. Experimental Design: We used human pancreatic cancer cells, both in vitro (cell culture experiments) and in vivo (xenograft experiments), to demonstrate the role of NAD synthesis and degradation in tumor cell metabolism and growth. Results: We demonstrated that pharmacologic and genetic targeting of Nampt, the key enzyme in the NAD salvage synthesis pathway, inhibits cell growth and survival of pancreatic cancer cells. These changes were accompanied by a reduction of NAD levels, glycolytic flux, lactate production, mitochondrial function, and levels of ATP. The massive reduction in overall metabolic activity induced by Nampt inhibition was accompanied by a dramatic decrease in pancreatic tumor growth. The results of the mechanistic experiments showed that neither the NAD-dependent enzymes PARP-1 nor SIRT1 play a significant role on the effect of Nampt inhibition on pancreatic cancer cells. However, we identified a role for the NAD degradation pathway mediated by the NADase CD38 on the sensitivity to Nampt inhibition. The responsiveness to Nampt inhibition is modulated by the expression of CD38; low levels of this enzyme decrease the sensitivity to Nampt inhibition. In contrast, its overexpression decreased cell growth in vitro and in vivo, and further increased the sensitivity to Nampt inhibition. Conclusions: Our study demonstrates that NAD metabolism is essential for pancreatic cancer cell survival and proliferation and that targeting NAD synthesis via the Nampt pathway could lead to novel therapeutic treatments for pancreatic cancer. Clin Cancer Res; 20(1); 120-30.

Original languageEnglish (US)
Pages (from-to)120-130
Number of pages11
JournalClinical Cancer Research
Volume20
Issue number1
DOIs
StatePublished - Jan 1 2014

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Pancreatic Neoplasms
NAD
Neoplasms
Growth
Therapeutics
Cell Survival
Enzymes
NAD+ Nucleosidase
Heterografts
Lactic Acid
Research Design
Cell Culture Techniques
Adenosine Triphosphate
Cell Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Chini, C. C. S., Gonzalez Guerrico, A. M., Nin, V., Camacho-Pereira, J., Escande, C., Barbosa, M. T., & Chini, E. N. (2014). Targeting of NAD metabolism in pancreatic cancer cells: Potential novel therapy for pancreatic tumors AC. Clinical Cancer Research, 20(1), 120-130. https://doi.org/10.1158/1078-0432.CCR-13-0150

Targeting of NAD metabolism in pancreatic cancer cells : Potential novel therapy for pancreatic tumors AC. / Chini, Claudia C S; Gonzalez Guerrico, Anatilde M.; Nin, Veronica; Camacho-Pereira, Juliana; Escande, Carlos; Barbosa, Maria Thereza; Chini, Eduardo Nunes.

In: Clinical Cancer Research, Vol. 20, No. 1, 01.01.2014, p. 120-130.

Research output: Contribution to journalArticle

Chini, CCS, Gonzalez Guerrico, AM, Nin, V, Camacho-Pereira, J, Escande, C, Barbosa, MT & Chini, EN 2014, 'Targeting of NAD metabolism in pancreatic cancer cells: Potential novel therapy for pancreatic tumors AC', Clinical Cancer Research, vol. 20, no. 1, pp. 120-130. https://doi.org/10.1158/1078-0432.CCR-13-0150
Chini CCS, Gonzalez Guerrico AM, Nin V, Camacho-Pereira J, Escande C, Barbosa MT et al. Targeting of NAD metabolism in pancreatic cancer cells: Potential novel therapy for pancreatic tumors AC. Clinical Cancer Research. 2014 Jan 1;20(1):120-130. https://doi.org/10.1158/1078-0432.CCR-13-0150
Chini, Claudia C S ; Gonzalez Guerrico, Anatilde M. ; Nin, Veronica ; Camacho-Pereira, Juliana ; Escande, Carlos ; Barbosa, Maria Thereza ; Chini, Eduardo Nunes. / Targeting of NAD metabolism in pancreatic cancer cells : Potential novel therapy for pancreatic tumors AC. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 1. pp. 120-130.
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