Beta-blockers
: functional properties and signalling mechanisms in cancer cell lines

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

β-Blockers or class II antiarrhythmics are antisympathetic nervous system agents that act by blocking β-adrenoceptors. Despite their common clinical use, little is known about the effects of β-blockers on free intracellular calcium (Ca2+i), an important cytosolic second messenger and a key regulator of cell function. Together with the transcription factor co-activator β-catenin, Ca2+i is also a key transducer of Wnt signalling pathways, which control numerous biological processes including cancer development and progression. Although used primarily to treat cardiac conditions, several epidemiological studies have linked the use of β-blockers with a lower incidence of cancer progression and mortality for various cancers, including prostate cancer. The mechanisms of action of β-blockers in cancer cells are still poorly understood. In this thesis, I explored the in vitro functional properties of several β-blockers and their potential to regulate Wnt signalling, using a combination of live cell calcium imaging, patch clamp electrophysiology, and molecular biology techniques. First, I characterised the activation of free Ca2+i release and the regulation of cell growth by six β-blockers in PC3 and LNCaP prostate cancer and MCF7 breast cancer cell lines. Second, I investigated the mechanisms by which propranolol activates Ca2+i stores in PC3 cells and the regulation of whole-cell currents by this β-blocker. Third, I evaluated the effects of propranolol on Wnt signalling pathways, focusing on the intracellular Wnt transducers Ca2+i and β-catenin and the whole-cell currents activated by Wnts. Propranolol suppressed cancer cell growth in a concentration dependent manner by inducing apoptosis and cell cycle arrest, whereas the other five β-blockers examined did not affect cell growth. Moreover, propranolol was the only β-blocker studied that activated the release of free Ca2+i in the cells, via a calcium-induced calcium release mechanism that could be mediated by the β2-adrenoceptor. The rise in Ca2+i levels led to the activation of a Ca2+-activated K+ current that hyperpolarised the cell membrane. Finally, propranolol inhibited some components of the Wnt signalling pathways: it precluded Wnt-induced Ca2+i release, reduced the translocation of β-catenin to the nucleus, and decreased the amplitude of the Wnt-induced currents. The differential actions of the β-blockers investigated may have implications on their pharmacology, and the new functional properties of propranolol described here add up to the emerging line of research that supports the repurposing of this β-blocker as a novel anti-cancer agent.
Date of Award1 Oct 2020
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorAamir Ahmed (Supervisor) & Prokar Dasgupta (Supervisor)

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