Inhibition of TRPM7 with waixenicin A reduces glioblastoma cellular functions. (December 2020)

• Record Type: Journal Article
• Authors: Wong, Raymond; Gong, Haifan; Alanazi, Rahmah; Bondoc, Andrew; Luck, Amanda; Sabha, Nesrin; Horgen, F. David; Fleig, Andrea; Rutka, James T.; Feng, Zhong-Ping; Sun, Hong-Shuo
• Is Part Of: Cell calcium. Volume 92(2020)
• Publication Date: 2020-12
• Subjects: GBM glioblastoma -- TRPM7 transient receptor potential melastatin 7 -- CNS central nervous system -- MPO multiparameter optimization -- BBB blood brain barrier -- FBS fetal bovine serum -- HEK human embryonic kidney; TRPM7 -- waixenicin A -- ion channels -- glioblastoma -- drug target; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2020.102307
• Languages: English
• ISSNs: 0143-4160

Abstract

Graphical Abstract: Inhibition of TRPM7 by waixenicin A reduces various cellular functions of GBM cells, including proliferation, viability, migration and invasion in both in vitro and in vivo assessments. Highlights: Application of the specific TRPM7 inhibitor waixenicin A in the GBM cell lines U251 and U87 in vitro : 1) decreases TRPM7 protein expression; and 2) inhibits endogenous TRPM7-like current; and 3) reduces cell viability, migration and invasion. In xenograft GBM mice, waixenicin A treatment downregulates activity of Ki-67, Akt and cofilin, while upregulating caspase 3 activity in vivo . The evidence here suggests that waixenicin A can potentially inhibit GBM growth and functions. Abstract: Glioblastoma (GBM) is the most common malignant primary brain tumour originating in the CNS. Median patient survival is <15 months with standard treatment which consists of surgery alongside radiation therapy and temozolomide chemotherapy. However, because of the aggressive nature of GBM, and the significant toxicity of these adjuvant therapies, long-term therapeutic effects are unsatisfactory. Thus, there is urgency to identify new drug targets for GBM. Recent evidence shows that the transient receptor potential melastatin 7 (TRPM7) cation channel is aberrantly upregulated in GBM and its inhibition leads to reduction of GBM cellular functions. This suggests that TRPM7 may be a potential drug target for GBM treatment. In this study, we assessed the effects of the specific TRPM7 antagonist waixenicin A on human GBM cell lines U87 or U251 both in vitro and in vivo . First, we demonstrated in vitro that application of waixenicin A reduced TRPM7 protein expression and inhibited the TRPM7-like currents in GBM cells. We also observed reduction of GBM cell viability, migration, and invasion. Using an intracranial xenograft GBM mouse model, we showed that with treatment of waixenicin A, there was increased cleaved caspase 3 activity, alongside reduction in Ki-67, cofilin, and Akt activity in vivo . Together, these data demonstrate higher GBM cell apoptosis, and lower proliferation, migration, invasion and survivability following treatment with waixenicin A.