Driving proteomic imbalance to combat Neurofibromatosis type I (NF1)-associated malignancy

Abstract

ABSTRACTUnlike genomic instability, the implications of proteomic instability in cancer remain ambiguous. By governing the proteotoxic stress response, heat shock factor 1 (HSF1) sustains proteomic stability upon environmental insults. Apart from its importance to stress resistance and survival, HSF1 is emerging as a powerful, generic oncogenic enabler. In the Neurofibromatosis type I (NF1)-deficient malignant peripheral nerve sheath tumor (MPNST) cells,HSF1depletion prompted protein polyubiquitination, aggregation, and even tumor-suppressive amyloidogenesis. In stark contrast,HSF1is dispensable for the proteome of non-transformed human Schwann cells. Mechanistically, in MPNST cells HSF1 defends the essential mitochondrial chaperone HSP60 against the direct assault from soluble amyloid oligomers. To survive and adapt to impaired protein quality, owing toHSF1deficiency, MPNST cells mobilized JNK to repress mTORC1 and protein translation, thereby attenuating protein quantity to alleviate proteomic imbalance. mTORC1 stimulation, via either pharmacological JNK blockade, geneticTSC2depletion, or supplement with the leucine analog NV-5138, markedly aggravated the proteomic imbalance elicited byHSF1deficiency. This profound proteomic imbalance instigated non-apoptotic cell death partly through unchecked amyloidogenesis. Thus, HSF1 safeguards the cancer proteome to enable the oncogenic potential of mTORC1. Counterintuitively, this proof-of-concept study highlights driving proteomic imbalance as a new therapeutic concept to combat malignancies.