mTORC1 promotes survival through translational control of Mcl-1

Abstract

Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway is a frequent occurrence in human cancers and a major promoter of chemotherapeutic resistance. Inhibition of one downstream target in this pathway, mTORC1, has shown potential to improve chemosensitivity. However, the mechanisms and genetic modifications that confer sensitivity to mTORC1 inhibitors remain unclear. Here, we demonstrate that loss of TSC2 in the E-myc murine lymphoma model leads to mTORC1 activation and accelerated oncogenesis caused by a defective apoptotic program despite compromised AKT phosphorylation. Tumors from Tsc2 ؉/؊ E-Myc mice underwent rapid apoptosis upon blockade of mTORC1 by rapamycin. We identified myeloid cell leukemia sequence 1 (Mcl-1), a bcl-2 like family member, as a translationally regulated genetic determinant of mTORC1-dependent survival. Our results indicate that the extent by which rapamycin can modulate expression of Mcl-1 is an important feature of the rapamycin response.rapamycin response ͉ Tsc2 loss ͉ apoptosis ͉ lymphoma ͉ Akt

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…Mcl-1 can counteract some of the pro-apoptotic events induced by c-Myc in the Em-Myc mice and result in lymphomas. 161,163,164 As mentioned before the Rheb GTPase is an activator of mTORC1. Rheb is highly expressed in some human lymphomas 31,[165][166][167] and other cancers.…”

“…One of the deregulated targets in the TSC2-(loss of heterozygosity)/Em-Myc lymphomas is Mcl-1 (ref. 164). Mcl-1 expression is induced and the mRNAs encoding Mcl-1 are translated by the increased activity of the mTORC1-eIF4E complex.…”

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

“…In addition, mTORC1 induces oxidative phosphorylation by facilitating YY1/PGC1α complex formation (Cunningham et al , 2007) and supports aerobic glycolysis (Duvel et al , 2010). In the Eμ‐Myc mouse model, mTORC1 activation was shown to accelerate lymphomagenesis by inhibiting Myc‐induced apoptosis through translational upregulation of the anti‐apoptotic protein myeloid cell leukemia 1 (Mcl1; Mills et al , 2008), suggesting a collaboration of Myc and mTORC1 in tumor initiation. On the contrary, MYC amplification was shown to confer resistance to mTORC1 inhibition through transcriptional activation of the eukaryotic translation initiation factor 4E (eIF4E), suggesting that mTORC1 function is not critical in the context of high MYC expression (Ilic et al , 2011).…”

Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation

“…It would therefore be interesting to investigate those proapoptotic members upon inhibition of glucose metabolism. Among the antiapoptotic members of the Bcl-2 family, Mcl-1 is of particular interest because (1) it contains a G þ C rich (>70%) 5 0 untranslated region (Mills et al, 2008) and (ii) given that Mcl-1 protein is highly regulated and rapidly degraded (Zhong et al, 2005;Maurer et al, 2006), inhibition of its synthesis would lead to a major decrease in protein level. Finally, several lines of evidence are in support of Mcl-1 regulation at the translational level.…”

“…Finally, several lines of evidence are in support of Mcl-1 regulation at the translational level. Studies have suggested that, in other contexts, Mcl-1 is a potential downstream target of eIF4E (Wei et al, 2006;Wendel et al, 2007;Mills et al, 2008). Recently Wei et al (2006) described the ability of rapamycin (mTOR inhibitor) to induce Mcl-1 but not Bcl-2 or Bcl-XL block in protein translation.…”