Transmembrane voltage potential is an essential cellular parameter for the detection and control of tumor development in aXenopusmodel

Abstract

SUMMARYUnderstanding mechanisms that orchestrate cell behavior into appropriately patterned tissues and organs within the organism is an essential element of preventing, detecting and treating cancer. Bioelectric signals (resting transmembrane voltage potential gradients in all cells) underlie an important and broadly conserved set of control mechanisms that regulate pattern formation. We tested the role of transmembrane potential in tumorigenesis mediated by canonical oncogenes in Xenopus laevis. Depolarized membrane potential (Vmem) was a characteristic of induced tumor-like structures (ITLSs) generated by overexpression of Gli1, KrasG12D, Xrel3 or p53Trp248. This bioelectric signature was also present in precursor ITLS sites. Vmem is a bioelectric marker that reveals ITLSs before they become histologically and morphologically apparent. Moreover, voltage was functionally important: overexpression of hyperpolarizing ion transporters caused a return to normal Vmem and significantly reduced ITLS formation in vivo. To characterize the molecular mechanism by which Vmem change regulates ITLS phenotypes, we performed a suppression screen. Vmem hyperpolarization was transduced into downstream events via Vmem-regulated activity of SLC5A8, a sodium-butyrate exchanger previously implicated in human cancer. These data indicate that butyrate, a histone deacetylase (HDAC) inhibitor, might be responsible for transcriptional events that mediate suppression of ITLSs by hyperpolarization. Vmem is a convenient cellular parameter by which tumors induced by human oncogenes can be detected in vivo and represents a new diagnostic modality. Moreover, control of resting membrane potential is functionally involved in the process by which oncogene-bearing cells depart from normal morphogenesis programs to form tumors. Modulation of Vmem levels is a novel and promising strategy for tumor normalization.

Local and long-range endogenous resting potential gradients antagonistically regulate apoptosis and proliferation in the embryonic CNS

“…Our previous study showed that V mem affects proliferation in the developing brain (Pai et al, 2015), as it does in a number of normal and neoplastic tissues (Blackiston et al, 2011, Blackiston et al, 2009, Chernet and Levin, 2013a, Ding et al, 2012, Higashimori and Sontheimer, 2007, Nilius and Wohlrab, 1992, Yang and Brackenbury, 2013. Hence, we next analyzed proliferation within the developing brain of Kv1.5 (hyperpolarizing) mRNA injected Xenopus embryos by immunostaining transverse sections through brain, for phosphorylated histone 3B (H3P; a proliferation marker; (Saka andSmith, 2001, Sanchez Alvarado, 2003).…”

“…Such patterns of resting potential within living tissues (bioelectric signals) have been studied in the context of their roles in cell migration and wound healing (Cao et al, 2013, Jaffe, 1979, McCaig et al, 2005, Richard B. Borgens, 1989, Zhao et al, 2006 and have long been proposed to direct growth and form in vivo (Burr, 1932). Bioelectric signals are implicated in vertebrate appendage regeneration , Tseng et al, 2010, cancer initiation and metastasis (Binggeli and Weinstein, 1986b, Blackiston et al, 2011, Brackenbury, 2012, Chernet and Levin, 2013b, Lobikin et al, 2012b, left-right patterning (Aw et al, 2008, Aw et al, 2010, Levin et al, 2002, planarian head induction (Beane et al, 2011, Beane et al, 2013, Marsh and Beams, 1947, and eye and brain formation (Nuckels et al, 2009, Pai et al, 2015, Pai et al, 2012a, Pai et al, 2012b. Thus bioelectric signals have been shown to be important regulators of large-scale patterning and tissue and organ identity (Levin, 2009, Levin, 2013a, Levin and Stevenson, 2012, Tseng and Levin, 2013a.…”

Does electromagnetic therapy meet an equivalent counterpart within the organism?

“…In embryogenesis resting potential values range from -8.5mV in the fertilized egg to -23mV in the fourcell till -25mV in the 16-cell frog embryo [5,9]. It is intriguing that, in general, malignant cancer cells (0-10 mV) as well as proliferating cells (CHO, 3T3, etc., -12 to -25 mV) have low cell membrane (resting) potentials [10,11].…”

“…In fact, the observation that the level of resting potential can switch from a diseased potential back to normal could be a very good argument for EMF / PEMF therapy [10]. Means, this therapy may trigger the tendency of the resting potential into the direction of a switch back from diseased to normal state.…”

Electriogram of Associative «Shu-Points» as A Diagnostic Tool for Diseases of the Internal Organs

“…Multiple recent studies have highlighted the role of bioelectric signals in large-scale pattern formation in the body's spatial structure and organs, and in organ phylogenesis and ontogenesis, during embryogenesis and regeneration [1][2][3][4][5]. These signals form one layer of physiological control and work in conjunction with biochemical and genetic pathways [6][7][8][9][10].…”