bims-lymeca 2023-05-28 papers

Issue of 2023‒05‒28
four papers selected by
Harilaos Filippakis
University of New England

Proc Natl Acad Sci U S A. 2023 05 30. 120(22): e2217425120

The KEAP1-NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis.

Athena Jessica S Ong, Cerys E Bladen, Tara A Tigani, Anthony P Karamalakis, Kimberley J Evason, Kristin K Brown, Andrew G Cox.

The maintenance of redox and metabolic homeostasis is integral to embryonic development. Nuclear factor erythroid 2-related factor 2 (NRF2) is a stress-induced transcription factor that plays a central role in the regulation of redox balance and cellular metabolism. Under homeostatic conditions, NRF2 is repressed by Kelch-like ECH-associated protein 1 (KEAP1). Here, we demonstrate that Keap1 deficiency induces Nrf2 activation and postdevelopmental lethality. Loss of viability is preceded by severe liver abnormalities characterized by an accumulation of lysosomes. Mechanistically, we demonstrate that loss of Keap1 promotes aberrant activation of transcription factor EB (TFEB)/transcription factor binding to IGHM Enhancer 3 (TFE3)-dependent lysosomal biogenesis. Importantly, we find that NRF2-dependent regulation of lysosomal biogenesis is cell autonomous and evolutionarily conserved. These studies identify a role for the KEAP1-NRF2 pathway in the regulation of lysosomal biogenesis and suggest that maintenance of lysosomal homeostasis is required during embryonic development.

Keywords: KEAP1; NRF2; TFEB/TFE3; lysosome; zebrafish

DOI: https://doi.org/10.1073/pnas.2217425120

Cell Rep. 2023 May 17. pii: S2211-1247(23)00530-2. [Epub ahead of print] 112519

PROX1 induction by autolysosomal activity stabilizes persister-like state of colon cancer via feedback repression of the NOX1-mTORC1 pathway.

Hirokazu Ohata, Daisuke Shiokawa, Hiroaki Sakai, Yusuke Kanda, Yoshie Okimoto, Syuzo Kaneko, Ryuji Hamamoto, Hitoshi Nakagama, Koji Okamoto.

Cancer chemoresistance is often attributed to slow-cycling persister populations with cancer stem cell (CSC)-like features. However, how persister populations emerge and prevail in cancer remains obscure. We previously demonstrated that while the NOX1-mTORC1 pathway is responsible for proliferation of a fast-cycling CSC population, PROX1 expression is required for chemoresistant persisters in colon cancer. Here, we show that enhanced autolysosomal activity mediated by mTORC1 inhibition induces PROX1 expression and that PROX1 induction in turn inhibits NOX1-mTORC1 activation. CDX2, identified as a transcriptional activator of NOX1, mediates PROX1-dependent NOX1 inhibition. PROX1-positive and CDX2-positive cells are present in distinct populations, and mTOR inhibition triggers conversion of the CDX2-positive population to the PROX1-positive population. Inhibition of autophagy synergizes with mTOR inhibition to block cancer proliferation. Thus, mTORC1 inhibition-mediated induction of PROX1 stabilizes a persister-like state with high autolysosomal activity via a feedback regulation that involves a key cascade of proliferating CSCs.

Keywords: CP: Cancer; NOX1; PROX1; autophagy; colon cancer; mTORC1; persister cells

DOI: https://doi.org/10.1016/j.celrep.2023.112519

Cytokine Growth Factor Rev. 2023 May 14. pii: S1359-6101(23)00021-7. [Epub ahead of print]

The role of Extracellular Vesicles in glycolytic and lipid metabolic reprogramming of cancer cells: Consequences for drug resistance.

Bárbara Polónia, Cristina P R Xavier, Joanna Kopecka, Chiara Riganti, M Helena Vasconcelos.

In order to adapt to a higher proliferative rate and an increased demand for energy sources, cancer cells rewire their metabolic pathways, a process currently recognized as a hallmark of cancer. Even though the metabolism of glucose is perhaps the most discussed metabolic shift in cancer, lipid metabolic alterations have been recently recognized as relevant players in the growth and proliferation of cancer cells. Importantly, some of these metabolic alterations are reported to induce a drug resistant phenotype in cancer cells. The acquisition of drug resistance traits severely hinders cancer treatment, being currently considered one of the major challenges of the oncological field. Evidence suggests that Extracellular Vesicles (EVs), which play a crucial role in intercellular communication, may act as facilitators of tumour progression, survival and drug resistance by modulating several aspects involved in the metabolism of cancer cells. This review aims to gather and discuss relevant data regarding metabolic reprograming in cancer, particularly involving the glycolytic and lipid alterations, focusing on its influence on drug resistance and highlighting the relevance of EVs as intercellular mediators of this process.

Keywords: Cancer; Drug Resistance; Extracellular Vesicles; Intercellular Communication; Metabolic Reprogramming

DOI: https://doi.org/10.1016/j.cytogfr.2023.05.001