RB/PLK1-dependent induced pathway by SLAMF3 expression inhibits mitosis and control hepatocarcinoma cell proliferation

Abstract

Polo-like kinase PLK1 is a cell cycle protein that plays multiple roles in promoting cell cycle progression. Among the many roles, the most prominent role of PLK1 is to regulate the mitotic spindle formation checkpoint at the M-phase. Recently we reported the expression of SLAMF3 in Hepatocytes and show that it is down regulated in tumor cells of hepatocellular carcinoma (HCC). We also show that the forced high expression level of SLAMF3 in HCC cells controls proliferation by inhibiting the MAPK ERK/JNK and the mTOR pathways. In the present study, we provide evidence that the inhibitory effect of SLAMF3 on HCC proliferation occurs through Retinoblastoma (RB) factor and PLK1-dependent pathway. In addition to the inhibition of MAPK ERK/ JNK and the mTOR pathways, expression of SLAMF3 in HCC retains RB factor in its hypophosphorylated active form, which in turn inactivates E2F transcription factor, thereby repressing the expression and activation of PLK1. A clear inverse correlation was also observed between SLAMF3 and PLK expression in patients with HCC.In conclusion, the results presented here suggest that the tumor suppressor potential of SLAMF3 occurs through activation of RB that represses PLK1. We propose that the induction of a high expression level of SLAMF3 in cancerous cells could control cellular mitosis and block tumor progression.

Hepatocyte SLAMF3 reduced specifically the multidrugs resistance protein MRP-1 and increases HCC cells sensitization to anti-cancer drugs

“…Expression of SLAMF3 is lost in tumor tissues as well as in cells from HCC cell lines compared to healthy tissues and cultured primary human hepatocytes PHH as we have reported previously [19, 20]. Here, we analyzed the expression of SLAMF3 and MRP-1 in cells from several HCC cell lines namely Huh-7, HepG2, Hep3B, SNU398, SNU449 and compared to PHH.…”

“…We also highlighted certain potential mechanisms responsible for the tumor suppressor effect of SLAMF3 by inhibiting the MAPK/ ERK1/2 phosphorylation and blocking the cell cycle at G2/M in an RB/PLK-1 dependent-manner [19, 20]. Herein, we show that establishing the high expression of SLAMF3 in cancerous cells inhibits specifically the expression of MRP-1.…”

“…We show that MDR, ABCG2 and MRP were highly expressed by Huh-7 cells (Figure 1a, 1b, 1c). We have earlier described the expression of SLAMF3 receptor in hepatocytes and shown that the high level expression of SLAMF3 inhibits proliferation in HCC cells [19, 20]. In order to clarify the link between the tumor suppressor effect of SLAMF3 and MDR expression in hepatocytes, we forced the SLAMF3 expression in Huh-7 cells and then quantified their expression.…”

“…On the other hand, SLAMF3 induced the cell cycle blockade at S-G2/M stage by PLK-1 inhibition. We previously evidenced that RB as cell cycle suppressor, is involved in the SLAMF3–induced cell cycle arrest [20]. Elevated MRP-1 expression probably results in a growth advantage to cancerous cells by pumping toxic substances out of the tumor cells and protecting cells against oxidative stress-related damage.…”

“…SLAMF3 expression also inhibits ERK1/2, JNK and mTOR pathways and controls tumor progression of HCC-xenografts in animal model [19]. In addition, we have also reported that SLAMF3 controls cell cycle progression in a RB/PLK-1 dependent manner [20]. The identification of SLAMF3 and its potential role in HCC cells proliferation control prompted us to investigate other potential pathways involved in its anti-proliferative effect.…”