Abstract 3696: Psychological stress inhibits, while GABA potentiates, the prevention of pancreatic cancer progression in xenografts by celecoxib
Authors: Al-Wadei Hussein A. , Ullah Mohammad F. , Al-Wadei Mohammed H. , Schuller Hildegard M. 
Published: August 2012

Pancreatic cancer has a poor prognosis and is associated with high levels of psychological distress. We have earlier shown that beta-adrenergic receptors, which are activated by stress neurotransmitters, regulate pancreatic cancer cells via cAMP-dependent signaling in vitro and that psychological distress promotes pancreatic cancer growth in vivo. The observation that psychological distress acts as an ancillary factor in growth promotion of pancreatic cancer have implications for cancer prevention strategies where stress initiated growth stimulus may retard the efficacy of cancer preventive regimens. Therefore this study tested the hypothesis that psychological stress inhibits the cancer preventive effects of celecoxib on pancreatic cancer progression whereas α-aminobutyric acid (GABA) which neutralizes the stress neurotransmitter stimulated cAMP signaling may potentiate the chemopreventive outcome of anti-cancer drugs. The effects of psychological distress in the absence and presence of treatment (with COX-2 inhibitor celecoxib alone / celecoxib with GABA co-adminstration) was tested in mice carrying xenograft from human pancreatic cancer cell line BxPC-3. Neuroendocrine responses (noradrenaline, adrenaline, cortisol & GABA), cancer stimulating factors (VEGF & prostaglandin PGE2) and levels of cAMP were measured by immunoassays in serum and xenograft tissue. Phosphorylation of nicotinic receptors (≥4 and α7), beta-adrenergic receptors, celecoxib targets (COX-2 & 5-lipoxygenase) and signaling proteins downstream of α-ARs were determined by semi-quantitative Western blots. The results show a significant inhibition of cancer preventive effects of celecoxib by psychological stress. By contrast, GABA significantly potentiated the preventive effects of celecoxib in this tumor model. The effector molecules of stress signaling via the cAMP pathway were downregulated by GABA and celecoxib additionally inhibited COX-2 and 5-lipoxygenase lead to significant inhibition of tumor growth in our xenografts model. Our findings identify the interruption of stress-induced c-AMP-dependent neuroendocrine stimulation as central regulator of pancreatic cancer that negatively impacts cancer prevention. In addition, our data identify the anti-stress GABA signaling as an effective adjuvant to standard interventions which in turn shows induce in the COX-2 phosphorylation and increase PGE2 level in the social stress groups which are inhibited by GABA or celecoxib or combination treatment. Better understanding in the above areas may help to develop new therapeutic for pancreatic cancer development. Grant Support: RC1CA144640 and R01CA042829 with the National Cancer Institute.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3696. doi:1538-7445.AM2012-3696