title: Inhibition of the transient receptor potential melastatin-2 channel causes increased DNA damage and decreased proliferation in breast adenocarcinoma cells.
abstract: Transient receptor potential, melastatin-2 (TRPM2) is a plasma membrane cation channel with important roles in sensory functions and promoting cell death. However, we demonstrated here that TRPM2 was present in the nuclei of MCF-7 and MDA-MB-231 human breast adenocarcinoma cells, and its pharmacologic inhibition or RNAi silencing caused decreased cell proliferation. Neither an effect on proliferation nor a localization of TRPM2 in the nucleus was observed in noncancerous HMEC and MCF-10A human mammary epithelial cells. Investigation of possible effects of TRPM2 function in the nucleus demonstrated that pharmacologic inhibition or RNAi silencing of TRPM2 in MCF-7 and MDA-MB-231 human breast adenocarcinoma cells caused up to 4-fold increases in DNA damage levels, as compared to noncancerous breast cells after equivalent treatments. These results indicate that TRPM2 has a novel nuclear function in human breast adenocarcinoma cells that facilitates the integrity of genomic DNA, a finding that is distinct from its previously reported role as a plasma membrane cation channel in noncancerous cells. In summary, we report here a novel effect promoted by TRPM2, where it functions to minimize DNA damage and thus may have a role in the protection of genomic DNA in breast cancer cells. Our study therefore provides compelling evidence that TRPM2 has a unique role in breast adenocarcinoma cells. Accordingly, these studies suggest that TRPM2 is a potential therapeutic target, where its pharmacologic inhibition may provide an innovative strategy to selectively increase DNA damage levels in breast cancer cells.
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Mandi M
authors.initials: MM
authors.lastname: Hopkins
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Mengwei
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University, Pullman, WA 99164, USA.
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Parker
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, Ohio Northern University, Ada, OH 45810, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Koh
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D020552:Comet Assay; D004249:DNA Damage / Q000502:physiology*; D006801:Humans; D015151:Immunoblotting; D034622:RNA Interference; D050053:TRPM Cation Channels / Q000378:metabolism*; D014162:Transfection
chemical_list: D050053:TRPM Cation Channels; C121934:TRPM2 protein, human