Intercepting neoplastic progression in lung malignancies via the beta adrenergic (β-AR) pathway: Implications for anti-cancer drug targets

Abstract

The understanding of signaling cascades involved in the induction, promotion, and progression of cancer, although advanced in recent years, is still incomplete. Tracing the imbalance of the impaired, physiologically-essential cellular signaling that drives the neoplastic process is a complex issue. This review discusses the role of the regulator of the fight or flight response, the beta-adrenergic signaling cascade, as a mediator of cancer growth and progression in in vitro and in vivo cancer models. We review a series of experiments from our own laboratory and those of others examining the contribution of this signaling network to lung and other human malignancies and thereby identifying potential targets for chemotherapeutic interventions. The stimulation of the β-adrenergic receptor by lifestyle and environmental factors, as well as a preexisting risk for neoplasm, activates downstream effector molecules (adenylyl cyclase/cAMP/PKA/CREB) concomitant to the transactivation of related pathways (EGFR) that lead to pro-oncogenic signaling; this β-adrenergic pathway thereby encourages cancer growth by evasion of apoptosis, invasion, angiogenesis, and metastasis. GABAergic signaling acts as an antagonist to the β-adrenergic cascade by intercepting adenylyl cyclase activation, and thereby neutralizing the pro-oncogenic effects of β-adrenergic stimulation. The regulation of cancer cell growth by neurobiological signals expands the possibilities for pharmacological interventions in cancer therapy.

Introduction

Cancer is a growing health problem around the world, particularly with the steady rise in life expectancy. Despite the efforts to limit the incidence of this global disease, cancer has been one of the leading causes of death for the last 50 years [1]. Cells and tissues are complex and have critical checkpoints to ensure normal growth. Normally, the division, differentiation, and death of cells are carefully regulated. All cancers start as a single cell that has lost control of its normal growth and replication processes. About 5–10% of cancers result directly from inheriting the genes associated with cancer risk [2], but the majority involves alterations to genetic material accumulated over time. Cell growth involves regulation of both transcriptional and translational processes, which are orchestrated by complex signaling pathways that are often interwoven. The cellular regulation of myriad cell signaling processes significant for normal (physiologically-desired) cell growth are subjected to environmental cues such as carcinogens, dietary factors, and stress. This environmental interference of the normal signaling pathways may alter inherent constraints leading to detrimental cross-talk, thereby making the cells acquire potential for indefinite proliferation.

Beta-adrenergic receptors (β-AR) are constitutively expressed in most mammalian cells and are associated with regulatory pathways operating under conditions of stress, classically defined as “fight or flight” responses [3]. There are three subtypes of β-AR, namely, β1-AR, β2-AR, and β3-AR, and each of these, either alone or in a concerted manner, responds to stimuli, resulting in the pharmacological and physiological effects observed in an individual cell. However, the distribution and the degree of expression of these subtypes may vary from tissue to tissue and in a given tissue from species to species [4]. The ubiquitous presence of β-AR in almost all mammalian cell types has attracted considerable interest toward studying the complex array of mechanisms and functions distinct from their classically-defined physiological actions. Evidence emerging from recent studies from our laboratory and those of others implicates β-ARs as important mediators of growth and/or invasiveness in a number of cancers, including lung, prostate, colon, stomach, breast, and ovary [5], [6], [7], [8], [9], [10]. Their stimulation is thought to be related to the growth and differentiation of certain tumor types [11], thus making β-ARs a promising target for the prevention and treatment of all of these cancer types. Enhanced β-AR expression [12] and overstimulation due to high levels of physiological agonists, adrenaline, and noradrenaline [13] in cancer cells are associated with hyperactivation of the beta-adrenergic pathway that may positively modulate the growth and progression of cancer thereby affecting clinical outcome.

The present article reviews the research conducted in our laboratory implicating β-adrenergic signaling cascades in cancer cell proliferation as a vital lead for therapeutic interventions in neoplastic processes in reference to lung cancer. Lung cancer is the leading cause of cancer death in the world in both men and women and has a mortality rate >95% within 1 year of diagnosis [14]; the lifestyle/environment associated with cigarette smoking is a dominant risk factor for this disease [15]. Four major types of lung cancers are prevalent: adenocarcinoma, small cell carcinoma, squamous cell carcinoma, and large cell carcinoma. It is understood that smoking increases the risk for the development of all of these lung cancers. However, adenocarcinoma, large cell carcinoma, and squamous cell carcinoma also develop in a significant population of non-smokers [16].