Altering calcium influx for selective destruction of breast tumor

BMC Cancer

Research Article

James Coad¹  Mackenzie Newman²  Han-Gang Yu²  Sarah McLaughlin³  Amanda Ammer³  Kathleen Brundage⁴  Karen Martin⁵ 

[1] Department of Pathology, West Virginia University, 26506, Morgantown, WV, USA;Department of Physiology and Pharmacology, West Virginia University, One Medical Center Drive, 26506, Morgantown, WV, USA;Mary Babb Randolph Cancer Center, West Virginia University, 26506, Morgantown, WV, USA;Mary Babb Randolph Cancer Center, West Virginia University, 26506, Morgantown, WV, USA;Department of Microbiology, Immunology and Cell Biology, West Virginia University, 26506, Morgantown, WV, USA;Mary Babb Randolph Cancer Center, West Virginia University, 26506, Morgantown, WV, USA;Department of Neurobiology and Anatomy, West Virginia University, 26506, Morgantown, WV, USA;

关键词: Breast cancer;    Triple-negative;    Bioelectricity;    Calcium channel;    Selective killing;    Caspase-3;   

DOI  :  10.1186/s12885-017-3168-x

 received in 2016-10-27, accepted in 2017-03-02,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundHuman triple-negative breast cancer has limited therapeutic choices. Breast tumor cells have depolarized plasma membrane potential. Using this unique electrical property, we aim to develop an effective selective killing of triple-negative breast cancer.MethodsWe used an engineered L-type voltage-gated calcium channel (Cec), activated by membrane depolarization without inactivation, to induce excessive calcium influx in breast tumor cells. Patch clamp and flow cytometry were used in testing the killing selectivity and efficiency of human breast tumor cells in vitro. Bioluminescence and ultrasound imaging were used in studies of human triple-negative breast cancer cell MDA-MB-231 xenograft in mice. Histological staining, immunoblotting and immunohistochemistry were used to investigate mechanism that mediates Cec-induced cell death.ResultsActivating Cec channels expressed in human breast cancer MCF7 cells produced enormous calcium influx at depolarized membrane. Activating the wild-type Cav1.2 channels expressed in MCF7 cells also produced a large calcium influx at depolarized membrane, but this calcium influx was diminished at the sustained membrane depolarization due to channel inactivation. MCF7 cells expressing Cec died when the membrane potential was held at -10 mV for 1 hr, while non-Cec-expressing MCF7 cells were alive. MCF7 cell death was 8-fold higher in Cec-expressing cells than in non-Cec-expressing cells. Direct injection of lentivirus containing Cec into MDA-MB-231 xenograft in mice inhibited tumor growth. Activated caspase-3 protein was detected only in MDA-MB-231 cells expressing Cec, along with a significantly increased expression of activated caspase-3 in xenograft tumor treated with Cec.ConclusionsWe demonstrated a novel strategy to induce constant calcium influx that selectively kills human triple-negative breast tumor cells.

【 授权许可】

CC BY   
© The Author(s). 2017