Abstract 3729: Inhibition of non small-cell lung cancer by stress reduction
Authors: Banerjee Jheelam , Papu John Arokya M. S , Schuller Hildegard M. 
Published: August 2015

Abstract
Non small-cell lung cancer (NSCLC) is the leading type of lung cancer with a poor prognosis. Smoking is a risk factor but NSCLC develops in a significant number of nonsmokers. We have reported that social stress significantly promoted the growth of NSCLC xenografts, a response mediated by multiple cAMP-driven signaling cascades downstream of Gαi-coupled beta-adrenergic receptors activated by the stress neurotransmitters norepinephrine and epinephrine and reversed by γ-aminobutyric acid (GABA) via Gαi-coupled GABA-B-receptor signaling. In addition, improved clinical outcomes in NSCLC patients with incidental beta-blocker therapy have been reported. These findings suggest that psychological stress with the associated increase in systemic stress neurotransmitter levels and suppression of physiological agonists for Gαi-coupled receptors may significantly contribute to the high incidence and poor therapeutic response of NSCLC. On the other hand, these findings suggest that stress reduction may have significant inhibitory effects on NSCLC. To test this hypothesis, we achieved stress reduction in athymic nude mice by maintaining the animals in larger cages and by providing them with several enrichment items, resulting in reduced systemic levels of corticosterone, norepinephrine and epinephrine while the levels of GABA and the physiological agonists for Gαi-coupled opioid receptors, dynorphin A and B and met-enkephalin increased. We found that stress reduction significantly inhibited the establishment of xenografts and significantly reduced xenograft sizes. Xenografts in the stress reduction group expressed lower levels of cAMP, VEGF and sonic hedgehog (SHH) accompanied by reduced protein expression of p-ERK, p-AKT, p-CREB, p-SRc and Gli1 while cleaved caspase-3 and p53 proteins were induced. Based on the observed reduction of the cancer stem cell markers SHH and Gli1 in xenograft tissues, we conducted additional mechanistic experiments with cancer stem cells enriched from three NSCLC cell lines under selective sphere formation conditions over 21 days with subcultures every seven days. We found that epinephrine significantly increased stem cell self renewal associated with increased intracellular cAMP, increased levels of the stem cell markers SHH and aldehyde dehydrogenase-1 and increased expression of Gli1. Simultaneous treatment of the enriched cancer stem cells with GABA or dynorphin B completely reversed all of these effects. We conclude that stress reduction can act as a powerful inhibitor of NSCLC by restoring cAMP homeostasis and should be incorporated as important component into existing NSCLC prevention and therapy protocols to improve clinical outcomes.
Supported in part by 5RC1CA144640 and State of Tennessee Center of Excellence for Human and Livestock Disease
Citation Format: Jheelam Banerjee, Arokya M. S Papu John, Hildegard M. Schuller. Inhibition of non small-cell lung cancer by stress reduction. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3729. doi:10.1158/1538-7445.AM2015-3729