SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness

Abstract

The sigma 1 receptor (Sig1R) is a stress-activated chaperone that regulates ion channels and is associated with pathologic conditions, such as stroke, neurodegenerative diseases, and addiction. Aberrant expression levels of ion channels and Sig1R have been detected in tumors and cancer cells, such as myeloid leukemia and colorectal cancer, but the link between ion channel regulation and Sig1R overexpression during malignancy has not been established. In this study, we found that Sig1R dynamically controls the membrane expression of the human voltage-dependent K þ channel human ether-a-go-go-related gene (hERG) in myeloid leukemia and colorectal cancer cell lines. Sig1R promoted the formation of hERG/b1-integrin signaling complexes upon extracellular matrix stimulation, triggering the activation of the PI3K/ AKT pathway. Consequently, the presence of Sig1R in cancer cells increased motility and VEGF secretion. In vivo, Sig1R expression enhanced the aggressiveness of tumor cells by potentiating invasion and angiogenesis, leading to poor survival. Collectively, our findings highlight a novel function for Sig1R in mediating crosstalk between cancer cells and their microenvironment, thus driving oncogenesis by shaping cellular electrical activity in response to extracellular signals. Given the involvement of ion channels in promoting several hallmarks of cancer, our study also offers a potential strategy to therapeutically target ion channel function through Sig1R inhibition. Cancer Res; 76(3); 607-18. Ó2015 AACR.

Application of Highly Immunocompromised Mice for the Establishment of Patient-Derived Xenograft (PDX) Models

“…Hairless mice have no noticeable immunocompromised phenotypes [38,39]. The SCID Hairless (SHO) mice (Charles River, MA, USA) and Hairless NOD/SCID mice (Envigo, Huntingdon, UK) were established by crossbreeding with hairless mice and used for in vivo imaging (Table 3) [40,41]; however, the engraftment efficiencies were lower than for NK-deficient strains [42]. Mice expressing fluorescence proteins are a powerful tool in cancer research, particularly for visualization of the tumor–host interaction [43].…”

Sigma Receptors as Endoplasmic Reticulum Stress “Gatekeepers” and their Modulators as Emerging New Weapons in the Fight Against Cancer

“…Recently, it was shown that S1R influences cancer cell behavior by modulating membrane electrical characteristics in response to the ECM properties and stimuli ( Crottès et al, 2011 ), thus activating the PI3K/AKT pathway, cell motility, and VEGF secretion ( Figure 5 ). In vivo , S1R expression increased tumor aggressiveness by enhancing invasion and angiogenesis, and reducing survival ( Crottés et al, 2016 ).…”

Ion channels expression and function are strongly modified in solid tumors and vascular malformations

“…As recently further demonstrated, several ion-channels are directly involved in controlling tumor—[ 17 ] as well as non-tumor angiogenesis [ 18 ]. Expression and activity of TRPV4 channel have been found suppressed in tumor endothelium [ 19 ], and its activation has been found to normalize tumor vessels [ 20 ]; inhibiting Cl − channel activity has anti-angiogenesis and anti-glioma properties [ 21 ]; finally, human voltage-dependent K + channel has been found associated with cancer aggressiveness and angiogenesis [ 22 ]. Therefore, ion-channels play a fundamental role in cancer progression as well as in angiogenesis.…”