1. Academic Validation
  2. HSF1-Mediated Control of Cellular Energy Metabolism and mTORC1 Activation Drive Acute T-Cell Lymphoblastic Leukemia Progression

HSF1-Mediated Control of Cellular Energy Metabolism and mTORC1 Activation Drive Acute T-Cell Lymphoblastic Leukemia Progression

  • Mol Cancer Res. 2020 Mar;18(3):463-476. doi: 10.1158/1541-7786.MCR-19-0217.
Binnur Eroglu  # 1 Junfeng Pang  # 1 Xiongjie Jin 1 Caixia Xi 1 Demetrius Moskophidis 2 3 Nahid F Mivechi 2 3 4
Affiliations

Affiliations

  • 1 Molecular Chaperone Biology, Medical College of Georgia, Georgia Cancer Center, Augusta University, Augusta, Georgia.
  • 2 Molecular Chaperone Biology, Medical College of Georgia, Georgia Cancer Center, Augusta University, Augusta, Georgia. nmivechi@augusta.edu dmoskofidis@augusta.edu.
  • 3 Department of Medicine, Augusta University, Augusta, Georgia.
  • 4 Department of Radiation Oncology, Augusta University, Augusta, Georgia.
  • # Contributed equally.
Abstract

Deregulated oncogenic signaling linked to PI3K/Akt and mTORC1 pathway activation is a hallmark of human T-cell acute leukemia (T-ALL) pathogenesis and contributes to leukemic cell resistance and adverse prognosis. Notably, although the multiagent chemotherapy of leukemia leads to a high rate of complete remission, options for salvage therapy for relapsed/refractory disease are limited due to the serious side effects of augmenting cytotoxic chemotherapy. We report that ablation of HSF1, a key transcriptional regulator of the chaperone response and cellular bioenergetics, from mouse T-ALL tumors driven by PTEN loss or human T-ALL cell lines, has significant therapeutic effects in reducing tumor burden and sensitizing malignant cell death. From a mechanistic perspective, the enhanced sensitivity of T-ALLs to HSF1 depletion resides in the reduced MAPK-ERK signaling and metabolic and ATP-producing capacity of malignant cells lacking HSF1 activity. Impaired mitochondrial ATP production and decreased intracellular amino acid content in HSF1-deficient T-ALL cells trigger an energy-saving adaptive response featured by attenuation of the mTORC1 activity, which is coregulated by ATP, and its downstream target proteins (p70S6K and 4E-BP). This leads to protein translation attenuation that diminishes oncogenic signals and malignant cell growth. Collectively, these metabolic alterations in the absence of HSF1 activity reveal Cancer cell liabilities and have a profound negative impact on T-ALL progression. IMPLICATIONS: Targeting HSF1 and HSF1-dependent cancer-specific anabolic and protein homeostasis programs has a significant therapeutic potential for T-ALL and may prevent progression of relapsed/refractory disease.

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