Upregulation of colonic ion channels in APC Min/+ mice

Abstract

The adenomatous polyposis coli (APC) tumor suppressor gene is mutated in almost all human colonic cancers. Disturbances in Na(+) absorption have been observed in colonic cancer, and ion channels such as ether a go-go (Eag) or Ca(2+)-sensitive BK channels have been recognized for their oncogenic potential. APC ( Min/+ ) mice have reduced APC expression and develop multiple intestinal neoplasias (Min). Ion channels in the colonic epithelium were examined using electrophysiology and molecular techniques. APC ( Min/+ ) mice developed intestinal neoplasia and experienced a significant weight loss. Due to intestinal bleedings, the hematocrit was largely reduced and plasma aldosterone levels were enhanced. Rectal potential measurements in vivo indicated an increase in amiloride-sensitive Na(+) absorption in APC ( Min/+ ) mice. Quantitative Ussing chamber studies demonstrated enhanced Na(+) absorption via epithelial Na(+) channels (ENaC) and suggested enhanced activity of oncogenic BK and Eag-1 channels. Patch clamp and fluorescence measurements on isolated crypts suggested enhanced K(+) channel activity in the surface epithelium. ENaC-mRNA and membrane protein expression was enhanced in colonic surface epithelial cells. The data suggest that reduced expression of the APC gene with upregulation of the downstream proteins Akt and mTOR and subsequent hyperaldosteronism is paralleled by upregulation of oncogenic potassium channels and enhanced colonic Na(+) absorption.

High-Content siRNA Screen Reveals Global ENaC Regulators and Potential Cystic Fibrosis Therapy Targets

“…CNTFR effects were further validated by its overexpression in Xenopus oocytes, which when coexpressed with ENaC enhanced Amil-sensitive conductance ( Figures 5C and 5D). Notably, 48 hr incubation of oocytes with the cytokine CNTF (CNTFR ligand) further increased the Amil-sensitive conductance, whereas inhibition of mTOR by rapamycin strongly inhibited ENaC ( Figure 5E) (Koehl et al, 2010;Ousingsawat et al, 2008). Thus, CNTF/ CNTFR appears be a novel pathway regulating ENaC operating through mTOR (Lu et al, 2010).…”

“…Although data here do not fully explore the intracellular pathways leading to ENaC activation through CNTFR, they strongly suggest that CNTFR operates through the mTOR pathway. In fact, earlier studies in mice with enhanced mTOR activity caused by reduced expression of the tumor suppressor APC, demonstrated pronounced upregulation of ENaC (Ousingsawat et al, 2008). This is probably due to upregulation of the transcriptional elongation factor elF4F, which is also in charge of postnatal ENaC upregulation (Otulakowski et al, 2007).…”

Rapamycin inhibits oncogenic intestinal ion channels and neoplasia in APCMin/+ mice

“…We conducted an in-depth analysis regarding the potential effects of rapamycin on oncogenic ion channels. Indeed, a substantial body of evidence exists for the oncogenic function of voltage-gated (Kv) and Ca 2 þ -activated (BK) K þ channels in colonic cancer and other tumors (Yao and Kwan, 1999;Pardo et al, 1999;Pardo et al, 2005;Ousingsawat et al, 2007;Ousingsawat et al, 2008). K þ channels control proliferation by controlling cell cycle and essential homeostatic parameters, such as intracellular Ca 2 þ , pH and cell volume (Schreiber, 2005).…”

Introducing, OncoTarget

“…Knockdown of MRP4 could attenuate the expression of p-CREB and COX-2, affecting PGE 2 synthesis [41]; however, whether it involves ENaC was not investigated. Of note, the potential role of ENaC in the development and progression of multiple cancers has recently been recognized [44][45][46][47]. Therefore, the capacity of MRP4 in regulating ENaC-dependent signaling pathways during embryo implantation as demonstrated presently may provide new insights into the understanding of MRP4/ENaC related signaling in cancers as well.…”