Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1

Abstract

Mutations in neurofibromin, a Ras GTPase-activating protein, lead to the tumor predisposition syndrome neurofibromatosis type 1. Here, we report that cells lacking neurofibromin exhibit enhanced glycolysis and decreased respiration in a Ras/ERK-dependent way. In the mitochondrial matrix of neurofibromin-deficient cells, a fraction of active ERK1/2 associates with succinate dehydrogenase (SDH) and TRAP1, a chaperone that promotes the accumulation of the oncometabolite succinate by inhibiting SDH. ERK1/2 enhances both formation of this multimeric complex and SDH inhibition. ERK1/2 kinase activity is favored by the interaction with TRAP1, and TRAP1 is, in turn, phosphorylated in an ERK1/2-dependent way. TRAP1 silencing or mutagenesis at the serine residues targeted by ERK1/2 abrogates tumorigenicity, a phenotype that is reverted by addition of a cell-permeable succinate analog. Our findings reveal that Ras/ERK signaling controls the metabolic changes orchestrated by TRAP1 that have a key role in tumor growth and are a promising target for anti-neoplastic strategies.

The Chaperone TRAP1 As a Modulator of the Mitochondrial Adaptations in Cancer Cells

“…(A) TRAP1 inhibits oxidative phosphorylation (OXPHOS) by interacting with both succinate dehydrogenase (SDH) and cytochrome oxidase, aka complex II and complex IV of the respiratory chain, respectively. SDH inhibition is enhanced by ERK1/2-dependent phosphorylation of TRAP1 and leads to succinate-dependent stabilization of the transcription factor HIF1α, which masters several pro-neoplastic programs (65, 69). Downregulation of cytochrome oxidase activity relies upon the inhibitory interaction between TRAP1 and Src (66).…”

Metabolic Plasticity of Tumor Cell Mitochondria

“…K-Ras-dependent transformation inhibits OXPHOS by down-regulating respiratory complex I content (97, 98). ERK, a crucial Ras effector that can locate in mitochondria (35, 99), decreases the activity of respiratory complex II, aka succinate dehydrogenase (SDH; see also section Post Translational Regulation In Cancer Metabolism) (100). Nonetheless, transformation by Ras does not abrogate OXPHOS activity, which still generates a large fraction of cellular ATP (101–103).…”

“…Inhibition of SDH by TRAP1 leads to succinate accumulation (133). Such an inhibition is further enhanced when ERK phosphorylates TRAP1, as in cells lacking the Ras GTPase-activating protein neurofibromin (100) that are characterized by deregulated induction of the Ras/ERK1/2 signaling pathway and form tumors in patients with the genetic syndrome neurofibromatosis type I (135). An increase in succinate levels induced by TRAP1 drives HIF1α stabilization independently of oxygen levels (136), i.e ., it generates conditions of pseudohypoxia, an adaptive feature of many tumors that allow them sustaining the neoplastic process even before hypoxic conditions are encountered by the growing malignancy.…”

“…An increase in succinate levels induced by TRAP1 drives HIF1α stabilization independently of oxygen levels (136), i.e ., it generates conditions of pseudohypoxia, an adaptive feature of many tumors that allow them sustaining the neoplastic process even before hypoxic conditions are encountered by the growing malignancy. The importance of providing such a metabolic adaptableness is highlighted by the observation that abrogating TRAP1 expression ablates tumorigenicity when different cell types are xenografted in mice (100, 133), even though the specific importance of TRAP1 in neoplastic growth could be context-dependent (132). …”

“…Mitochondrial ERK1/2 phosphorylates TRAP1, thus enhancing its inhibition of SDH. TRAP1 ablation or mutagenesis at the Ser residues targeted by ERK1/2 abrogates the tumorigenicity of cells lacking neurofibromin (100). …”