Acid-stimulated Ca2+ signals as a potential therapeutic target for the treatment of oesophageal cancer
Alana L. Cutliffe and Dr John J. Mackrill
Alana Cutliffe was awarded with Breakthrough Project Grant 2020, under the supervision of Dr. John Mackrill.
It is known that, when dissolved in water, calcium forms calcium ions (Ca2+). Inside cells, Ca2+ acts as a key signal, controlling almost every process from movement to metabolism and the expression of genes. However, excessively high concentrations of Ca2+ lead to cell death.
Worldwide, oesophageal cancer (OEC) is the sixth leading cause of cancer-related mortality and is poorly responsive to treatment [2]. OEC cells respond to changes in their environment, including alterations in acidity, with rises in intracellular Ca2+. Increased Ca2+ in OEC cells Ca2+ damages the DNA [3] and causes inflammation [4], both of which promote the development and progression of cancer. Little is known about which molecular mechanisms underlie these changes in Ca2+, but probably include pumps, (which increase the amount of Ca2+ within certain compartments of the cell) and channels (which are like “valves”) Consequently, our short-term aim is to identify which molecular mechanisms are involved in converting changes in acidity outside of OEC cells into Ca2+ signals within them. Ca2+ signals in response to acidity will be measured in OEC cells using a technique called fluorescent video microscopy: which records changes in the brightness of a Ca2+-sensing fluorescent dye placed within OEC cells, using a microscope. The mechanisms involved in these Ca2+ signals will be determined using drugs that inhibit them and by molecular approaches, to decrease their levels. This represents the first step achieving in our long-term goal of developing new types of anti-OEC chemotherapy, targeting mechanisms involved in generating acid-stimulated Ca2+ signals.
RESEARCH FINDINGS
Publications
Cutliffe AL, McKenna SL, Chandrashekar DS, Ng A, Devonshire G, Fitzgerald RC, O’Donovan TR, Mackrill JJ. Alterations in the Ca2+ toolkit in oesophageal adenocarcinoma. Explor Target Antitumor Ther. 2021;2(6):543-575. doi: 10.37349/etat.2021.00063. Epub 2021 Dec 31. PMID: 36046118; PMCID: PMC9400700.
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Start year
2020
End year
2021
Principal Investigator
Dr. John Mackrill
Researcher
Alana Cutliffe
Institution
University College Cork
Grant Funding
Breakthrough Project Grant
Linked Breakthrough Cancer Research Priorities
Increase research investment into poor prognosis cancers and currently incurable cancers prioritising lung, oesophageal, ovarian, pancreatic, brain, liver and stomach cancers.
Fund the discovery and development of new therapeutics, surgical approaches and technologies, including biological and immune approaches, to improve cancer treatment.
Fund research which aims to improve the effectiveness or specificity of current cancer therapies including investing in biomarkers discovery, nutrition and therapeutic delivery.