PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR

Abstract

Loss of the promyelocytic leukaemia (PML) tumour suppressor has been observed in several human cancers. The tumour-suppressive function of PML has been attributed to its ability to induce growth arrest, cellular senescence and apoptosis. Here we identify PML as a critical inhibitor of neoangiogenesis (the formation of new blood vessels) in vivo, in both ischaemic and neoplastic conditions, through the control of protein translation. We demonstrate that in hypoxic conditions PML acts as a negative regulator of the synthesis rate of hypoxia-inducible factor 1alpha (HIF-1alpha) by repressing mammalian target of rapamycin (mTOR). PML physically interacts with mTOR and negatively regulates its association with the small GTPase Rheb by favouring mTOR nuclear accumulation. Notably, Pml-/- cells and tumours display higher sensitivity both in vitro and in vivo to growth inhibition by rapamycin, and lack of PML inversely correlates with phosphorylation of ribosomal protein S6 and tumour angiogenesis in mouse and human tumours. Thus, our findings identify PML as a novel suppressor of mTOR and neoangiogenesis.

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

“…As 2 O 3 reduced PML levels in leukemic CICs and decreased the number of quiescent CIC in the absence of the induction of apoptosis. [191][192][193] Consistent with these results, the long-term maintenance of the CIC was dramatically suppressed. The authors examined the effects of cytosine arabinoside and As 2 O 3 on leukemia CICs.…”

“…Targeting of PML also leads to increased HSC cycling and to mTOR-mediated HSC depletion. [191][192][193] PML is highly expressed in HSCs and decreases as the HSC differentiate. PML loss or lower expression predicts a better prognosis in chronic myeloid leukemia.…”

“…PML loss or lower expression predicts a better prognosis in chronic myeloid leukemia. 192,193 PML is a negative regulator of mTOR 193 and is important in HSC maintenance. PML À/À HSC lack long-term repopulating capacity, which is likely due to defective maintenance of quiescence.…”

Modulation of M2‐type pyruvate kinase activity by the cytoplasmic PML tumor suppressor protein

“…Since significant amounts of cPML were detected in parental MCF-7 cells, cPML might more effectively regulate proliferation of other types of cells which have lower amounts of cPML. Recently, Bernardi et al (2006) demonstrated that nuclear PML suppresses HIF-1 translation by recruiting mTOR to PML-NBs, leading to the suppression of tumor cell growth under hypoxia. Thus, the over-expression of cPML may cause mTOR to be anchored in the cytoplasm, and counteract the tumor suppressor function of nuclear PML during hypoxia.…”

Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia

“…30 Cell response to hypoxia comprises upregulation of hypoxia-inducible factor-1a (HIF-1a), which is under control of mTORC1. 31 HIF-1a then induces transcription of a number of genes, including VEGF-A, 32 CXCR4, the receptor for CXCL12 chemokine 33 and PIM-1 kinase. 34 Interactions between CXCR4 and CXCL12 strongly contribute to drug resistance of leukemic cells.…”