bims-lymeca 2022-06-12 papers

on Lysosome metabolism in cancer

Issue of 2022–06–12
two papers selected by
Harilaos Filippakis, University of New England

NUPR1 promotes the proliferation and migration of breast cancer cells by activating TFE3 transcription to induce autophagy.
Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.

Exp Cell Res. 2022 Jun 02. pii: S0014-4827(22)00227-0. [Epub ahead of print] 113234

NUPR1 promotes the proliferation and migration of breast cancer cells by activating TFE3 transcription to induce autophagy.

Heng Xiao, Jing Long, Xiang Chen, Mi-Duo Tan.

  Recurrence and metastasis affect the survival rate of breast cancer patients. The fundamental reason lies in the lack of understanding of the mechanism of breast cancer metastasis. In this study, the proliferation, migration and invasion abilities of breast cancer cells were evaluated. The mechanism of NUPR1/TFE3 signaling pathway on autophagy-related proteins and migration-invasion-related proteins was examined in cell model in vitro. The effects of NUPR1 on malignancy formation and metastasis were investigated in vivo. We found that NUPR1 was upregulated in breast cancer cells and tissues. NUPR1 knockdown inhibited the proliferation, migration and invasion of ZR-75-30 cells and inhibited malignancy formation and metastasis in vivo. Mechanically, NUPR1 promoted autophagy by activating of TFE3 transcription, thereby regulating breast cancer metastasis. This paper indicates that NUPR1 activates autophagy through the TFE3 signaling pathway to promote breast cancer metastasis, and provides a biological basis for the intervention of blocking distant metastasis.

Keywords:  Autophagy; Breast cancer; NUPR1; TFE3

DOI:  https://doi.org/10.1016/j.yexcr.2022.113234
Nat Cancer. 2022 Jun 09.

Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.

Ali Vaziri-Gohar, Joel Cassel, Farheen S Mohammed, Mehrdad Zarei, Jonathan J Hue, Omid Hajihassani, Hallie J Graor, Yellamelli V V Srikanth, Saadia A Karim, Ata Abbas, Erin Prendergast, Vanessa Chen, Erryk S Katayama, Katerina Dukleska, Imran Khokhar, Anthony Andren, Li Zhang, Chunying Wu, Bernadette Erokwu, Chris A Flask, Mahsa Zarei, Rui Wang, Luke D Rothermel, Andrea M P Romani, Jessica Bowers, Robert Getts, Curtis Tatsuoka, Jennifer P Morton, Ilya Bederman, Henri Brunengraber, Costas A Lyssiotis, Joseph M Salvino, Jonathan R Brody, Jordan M Winter.

Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.

DOI: https://doi.org/10.1038/s43018-022-00393-y