Multidrug resistance protein 3 loss promotes tumor formation by inducing senescence escape

Abstract

Oncogenic-stress-induced senescence (OIS) is a stress response allowing normal cells, when receiving oncogenic signals, to stably arrest their proliferation. OIS thus acts to prevent aberrant cell proliferation and tumor formation. To identify novel tumor suppressive pathways, we have recently completed a loss-of-function genetic screen to identify novel genes promoting escape from OIS and thus, potentially, tumor formation when their functions are lost. Using this approach, we unexpectedly found that loss of function of the multidrug resistance protein 3 (MRP3 or ABCC3) promotes escape from OIS in human epithelial cells. Importantly, ABCC3 expression is reduced in human skin tumors, and ABCC3-knockout mice display increased sensitivity to RAS-induced skin carcinogenesis, concomitantly with decreased OIS. ABCC3 participates in resistance to chemotherapy via its transporter activity. Our data show that this transporter activity is involved in ABCC3-induced senescence, demonstrating that this protein has a complex role in cancer, since its loss of function may promote escape from OIS and tumor formation whereas its gain of function promotes resistance to chemotherapy.

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.…”

Transport and senescence

“…To understand the mechanism giving ABCC3 these tumor suppressive properties, we investigated its transport function. Whereas overexpression of ABCC3 sensitized cells to OIS, overexpression of a mutant form of ABCC3 whose transport function is altered was unable to sensitize cells to OIS [5]. Altogether, these observations led us to speculate that ABCC3 transporter excretes outside the cells macromolecules necessary for OIS establishment.…”

Transcriptional repression of DNA repair genes is a hallmark and a cause of cellular senescence

“…To gain some insight into the mechanisms regulating cellular senescence in epithelial cells, which are at the origin of most cancers, we characterized the transcriptome of immortalized human mammary epithelial cells expressing a fused inducible (by 4-OHT) MEK:ER oncogene (HMEC-MEK), a model of oncogene-induced senescence (OIS) that we have described previously 17 – 19 . Gene ontology (GO) analyses revealed that expression of numerous genes involved in pathways covering different DNA repair systems were strongly downregulated during OIS in HMEC-MEK cells (Table 1 ).…”