Potassium Channel KCNA1 Modulates Oncogene-Induced Senescence and Transformation

Abstract

Oncogene-induced senescence (OIS) constitutes a failsafe program that restricts tumor development. However, the mechanisms that link oncogenesis to senescence are not completely understood. We carried out a loss-of-function genetic screen that identified the potassium channel KCNA1 as a determinant of OIS escape that can license tumor growth. Oncogenic stress triggers an increase in KCNA1 expression and its relocation from the cytoplasm to the membrane. Mechanistically, this relocation is due to a loss of protein kinase A (PKA)-induced phosphorylation at residue S446 of KCNA1. Accordingly, sustaining PKA activity or expressing a KCNA1 phosphomimetic mutant maintained KCNA1 in the cytoplasm and caused escape from OIS. KCNA1 relocation to the membrane induced a change in membrane potential that invariably resulted in cellular senescence. Restoring KCNA1 expression in transformation-competent cells triggered variation in membrane potential and blocked RAS-induced transformation, and PKA activation suppressed both effects. Furthermore, KCNA1 expression was reduced in human cancers, and this decrease correlated with an increase in breast cancer aggressiveness. Taken together, our results identify a novel pathway that restricts oncogenesis through a potassium channel-dependent senescence pathway. Cancer Res; 73(16); 5253-65. Ó2013 AACR.

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

“…We then used a model of OIS in human epithelial cells, a model we have extensively characterized (Lallet‐Daher et al., 2013; Wiel et al., 2014, 2016). These cells stably expressed both hTert to be immortalized and MEK:ER, a 4‐hydroxytamoxifen (4‐OHT) inducible oncogene (HEC‐TM cells), to induce the oncogenic signal.…”

“…For example, our microarray analyses by GSEA display enrichment in induction of calcium and potassium voltage‐dependent channels (data not shown) in OIS cells. In addition, an involvement of KCNA1 potassium channel has also been shown to regulate senescence (Lallet‐Daher et al., 2013; Wiel et al., 2014, 2016). Thus, several channels should contribute to plasma membrane potential during OIS, together with SCN9A sodium channels.…”

Endoplasmic reticulum calcium release through ITPR2 channels leads to mitochondrial calcium accumulation and senescence

“…We have identified multiple potential shRNA-targeted genes. Details of the screening strategy, methods and results were previously described in Lallet-Daher et al 17 We were particularly interested in focusing our work on the ITPR2 calcium channel. This channel is a member of the inosotol 1,4,5-triphosphate (IP3) receptor (ITPR) family, composed of two other members: ITPR1 and ITPR3, the most ubiquitously expressed family of calciumreleased channel of the ER.…”

“…We next wanted to determine the altered localization of calcium in senescent cells. We hypothesized that the mitochondria would be involved in this redistribution, since calcium release by the ER can be transferred to mitochondria 19 , and also because the MCU 20,21 , a key component in mitochondrial calcium uptake, was identified in the genetic screen 17 . To examine the localization of calcium dots in senescent cells, we used an red fluorescent protein (RFP)-tagged mitochondrial protein which showed that the calcium dots co-localize with the mitochondria during OIS (Fig.…”

Targeting potassium channels in cancer

“…Recent work has demonstrated that oncogenic stress increases KCNA1 expression and promotes its relocation from the cytoplasm to the plasma membrane, which is required for oncogene-induced senescence. Ectopic expression of KCNA1 inhibits RAS-induced transformation, whereas a reduction of KCNA1 expression correlates with an increase in breast cancer aggressiveness (Lallet-Daher et al, 2013). These findings suggest that KCNA1 may restrict tumor growth through a potassium channel-dependent senescence pathway, and the functional significance of potassium channel during tumorigenesis could vary with the channel and/or cancer type.…”