Mithramycin A activates Fas death pathway in leukemic cell lines

Abstract

Mithramycin A (MMA, trade name Plicamycin) can facilitate TNFα-(Tumor Necrosis Factor) and Fas ligand-induced apoptosis. Besides, several drugs play their anticancer effect through Fas apoptotic pathway. So we investigated the effect of MMA on Fas signaling. In this study we show that MMA induces apoptosis in Fas sensitive Jurkat cells and Fas resistant KG1a cells. This effect involves Fas apoptotic pathway: cell exposure to MMA leads to Fas clustering at the cell surface, DISC (Death Inducing Signaling Complex) formation and caspase cleavage. This phenomenon is independent of Fas ligand/Fas interaction and blockade of Fas death pathway partially inhibits MMA-induced apoptosis. Moreover the activation of Fas apoptotic pathway by MMA is correlated to the modulation of c-Flip L expression. Finally, pre-treatment with sub-lethal doses of MMA sensitizes KG1a cells to chemotherapeutic agents. Thus all these results may have important implications to improve clinical treatments.

Sp1 expression regulates lung tumor progression

“…Because of serious cell death and activation of proapoptotic proteins upon MMA treatment (data not shown), it is difficult to evaluate its effect on invasive activity of lung cancer cells. In addition, according to previous studies, MMA still contains other functions such as facilitating apoptosis through activating Fas pathway (Duverger et al , 2004; Leroy et al , 2006). Therefore, another effect(s) of MMA except affecting Sp1-binding activity might also be involved in the lung cancer tumorigenesis, such as downregulation of DNA methytransferase 1 and MUC5A, both of which are related to tumor malignancy (Lin et al , 2007; Lee et al , 2011).…”

Mithramycin A sensitizes cancer cells to TRAIL-mediated apoptosis by down-regulation of XIAP gene promoter through Sp1 sites

“…Its mechanism of action has been proposed to interact with GC-rich domains of DNA contained in genes promoters (9), leading to gene transcription modulation, such as multidrug resistance gene (10), c-myc, or h-ras (11). It has recently been shown that mithramycin A can sensitize tumor cells to apoptosis induced by tumor necrosis factor-a and anti-Fas antibody (12,13). However, the underlying mechanisms of mithramycin A -induced sensitization are not well understood.…”

Therapeutic restoration of cytolytic and suicidal cell molecular machineries favours disease healing

“…Interestingly, the above mentioned treatments are able to favour disease healing, because some of them restore AlCC by inducing granzyme-mediated [1] or Fas-mediated [2][3][4][5] cytolytic pathways, whereas others restore AcCS [6,7] .…”

“…This is likely to be the case, in our opinion. In fact, a number of drugs have recently been shown to cure disease while exerting cytolytic or suicidal pathways [1][2][3][4][5][6][7] : indeed, such drugs restored machineries belonging to AlCC [1][2][3][4][5] or machineries belonging to AcCS [6,7] . In conclusion, it seems possible, in our opinion, to anticipate that, in next years, a lot of diseases ( Table 1 ) could be cured by treatments able to restore the molecular machineries operating in AlCC or in AcCS.…”

“…Several drugs, including FK-506 [1] , mythramicin A [2] , bortezomib [3] , rituximab [4,5] , safrole oxide [6] , IL-2 [7] , have recently been shown to favour improvement of different diseases by activating cytolytic [1][2][3][4][5] or suicidal [6,7] cell molecular machineries. This apparent paradox, however, can be explained, in our opinion, by suggesting that such drugs are able to restore cytolytic or suicidal pathways that, under normal conditions, prevent the onset of a number of diseases ( Figures 1 and 2 ).…”