Derivatives of Dictyostelium Differentiation-Inducing Factor-3 Promote Autophagic Flux, Mitochondrial Dysfunction and Iron-Associated Oxidative Stress
4 affiliations
- 1Laboratory of Food and Life Science, Institute of Human Sciences, Waseda University, Saitama 359-1192, Japan
- 2Department of Food and Health Sciences, International College of Arts and Sciences, Fukuoka Women’s University, Fukuoka 813-8529, Japan
- 3Division of Natural Medicines, Faculty of Pharmacy, Keio University, Tokyo 105-8512, Japan
- 4Faculty of Health and Sports Science, Juntendo University, Chiba 270-1695, Japan
Abstract
Novel anticancer agents are needed to overcome therapeutic resistance, and autophagy represents a promising target. The chlorinated alkylphenones Dictyostelium differentiation-inducing factors 1 and 3 (DIF-1 and DIF-3) and their derivatives exert anti-proliferative and anti-metastatic effects; however, their molecular mechanisms remain incompletely understood. Using the GFP-LC3-RFP-LC3ΔG autophagic flux reporter, we identified Bu-DIF-3 and CP-DIF-3 as autophagy-promoting derivatives and characterized their actions principally in HeLa cells, with selected autophagy and AMP-activated protein kinase (AMPK) measurements in HAP1 cells. Both suppressed mTORC1 signaling, activated AMPK, and reduced mitochondrial membrane potential (MMP). Bu-DIF-3 additionally induced reactive oxygen species and redox stress response genes, including SLC7A11 and CHAC1. SLC7A11 induction may reflect a compensatory antioxidant response. Unlike CP-DIF-3, Bu-DIF-3 increased the FerroOrange-detectable labile Fe2+ signal, and deferoxamine partially restored the reduced MTT signal, supporting possible iron involvement in reduced metabolic activity. Thus, modification of the DIF-3 methoxy group modulates autophagy-promoting activity and associated stress responses. Bu-DIF-3 was associated with oxidative stress and altered labile Fe2+ homeostasis; whether a ferroptosis-related mechanism contributes remains unresolved. These findings provide a cellular basis for further evaluation of Bu-DIF-3 and related DIF derivatives.
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BibTeX
@article{cai2026derivatives,
title = {{Derivatives of Dictyostelium Differentiation-Inducing Factor-3 Promote Autophagic Flux, Mitochondrial Dysfunction and Iron-Associated Oxidative Stress}},
author = {Yue Cai and Ryu Yamada and Yuki Marugame and Satoshi Yano and Fumihiko Okumura and Haruhisa Kikuchi and Yuzuru Kubohara and Taichi Hara},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209380},
url = {https://www.mdpi.com/1422-0067/27/20/9380},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Derivatives of Dictyostelium Differentiation-Inducing Factor-3 Promote Autophagic Flux, Mitochondrial Dysfunction and Iron-Associated Oxidative Stress
AU - Yue Cai
AU - Ryu Yamada
AU - Yuki Marugame
AU - Satoshi Yano
AU - Fumihiko Okumura
AU - Haruhisa Kikuchi
AU - Yuzuru Kubohara
AU - Taichi Hara
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209380
UR - https://www.mdpi.com/1422-0067/27/20/9380
AB - Novel anticancer agents are needed to overcome therapeutic resistance, and autophagy represents a promising target. The chlorinated alkylphenones Dictyostelium differentiation-inducing factors 1 and 3 (DIF-1 and DIF-3) and their derivatives exert anti-proliferative and anti-metastatic effects; however, their molecular mechanisms remain incompletely understood. Using the GFP-LC3-RFP-LC3ΔG autophagic flux reporter, we identified Bu-DIF-3 and CP-DIF-3 as autophagy-promoting derivatives and characterized their actions principally in HeLa cells, with selected autophagy and AMP-activated protein kinase (AMPK) measurements in HAP1 cells. Both suppressed mTORC1 signaling, activated AMPK, and reduced mitochondrial membrane potential (MMP). Bu-DIF-3 additionally induced reactive oxygen species and redox stress response genes, including SLC7A11 and CHAC1. SLC7A11 induction may reflect a compensatory antioxidant response. Unlike CP-DIF-3, Bu-DIF-3 increased the FerroOrange-detectable labile Fe2+ signal, and deferoxamine partially restored the reduced MTT signal, supporting possible iron involvement in reduced metabolic activity. Thus, modification of the DIF-3 methoxy group modulates autophagy-promoting activity and associated stress responses. Bu-DIF-3 was associated with oxidative stress and altered labile Fe2+ homeostasis; whether a ferroptosis-related mechanism contributes remains unresolved. These findings provide a cellular basis for further evaluation of Bu-DIF-3 and related DIF derivatives.
SN - 1422-0067
ER -