Synthetic Retinoid Kills Drug‐Resistant Cancer Stem Cells via Inducing RAR<i>γ</i>‐Translocation‐Mediated Tension Reduction and Chromatin Decondensation

Zhang, Yao; Dong, Qi; An, Quanlin; Zhang, Chumei; Mohagheghian, Erfan; Niu, Bing; Feng, Qi; Wei, Fuxiang; Chen, Sihan; Chen, Xinman; Wang, Anqi; Cao, Xin; Wang, Ning

doi:10.1002/advs.202203173

Cited by 6 publications

(4 citation statements)

References 54 publications

(85 reference statements)

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“…S11 ). Both chemicals are known to decondense the chromatin in living cells, observed by electron microscopy ( 18 , 19 ). In contrast, JIB-04, which condenses the chromatin, did not change the FRET efficiency of HP1α ( SI Appendix , Fig.…”

Section: Resultsmentioning

confidence: 99%

Mechanomemory in protein diffusivity of chromatin and nucleoplasm after force cessation

Rashid

Liu

Wang

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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It is known that external mechanical forces can regulate structures and functions of living cells and tissues in physiology and diseases. However, after cessation of the force, how structures are altered in response to the dynamics of the chromatin and molecules in the nucleoplasm remains elusive. Here, using single-molecule imaging approaches, we show that exogenous local forces via integrins applied for 2 to 10 min decondensed the chromatin and increased chromatin and nucleoplasm protein mobility inside the nucleus, leading to elevated diffusivity of single protein molecules in the nucleoplasm, tens of minutes after the cessation of force. Diffusion experiments with fluorescence correlation spectroscopy in live single cells show that the mechanomemory in chromatin and nucleoplasm protein diffusivity was regulated by nuclear pore complexes. Protein molecular dynamics simulation recapitulated the experimental findings in live cells and showed that nucleoplasm protein diffusivity was regulated by the number of nuclear pore complexes. The mechanomemory in elevated protein diffusivity of the nucleoplasm after force cessation represents a physical process that reverses protein–protein condensation in phase separation via unjamming of the chromatin. Our findings of mechanomemory in chromatin and nucleoplasm protein diffusivity suggest that the effect of force on the nucleus remains tens of minutes after force cessation and thus is more far-reaching than previously anticipated.

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Section: Resultsmentioning

confidence: 99%

Mechanomemory in protein diffusivity of chromatin and nucleoplasm after force cessation

Rashid

Liu

Wang

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…S1 ). Tazarotene is a receptor-selective aromatic RA that binds to the RAR and exerts biological effects by regulating gene transcription 13 . The structure of EYE-502 confers better water solubility.…”

Section: Resultsmentioning

confidence: 99%

A novel retinoic acid drug, EYE-502, inhibits choroidal neovascularization by targeting endothelial cells and pericytes

Shen

Ren

et al. 2023

Sci Rep

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Choroidal neovascularization (CNV) occurs in neovascular age-related macular degeneration (AMD) and often leads to permanent visual impairment. Intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is the gold standard for the treatment of CNV. However, anti-VEGF treatment did not always cause vision improvement and sometimes had detrimental effects on normal retinal tissues. Herein, we identified a novel retinoic acid drug, EYE-502, which had great therapeutic effects on CNV. Administration of EYE-502 could inhibit VEGF-induced dysfunction of endothelial cells (ECs) and reduce platelet-derived growth factor (PDGF)-induced recruitment of pericytes to ECs in vitro. Administration of EYE-502 could reduce the area of choroidal sprouting and laser-induced CNV, exhibiting similar anti-angiogenic effects as aflibercept. Moreover, administration of EYE-502 could reduce pericyte coverage in the sprouting vessels and choroidal neovascularization. Mechanistically, EYE-502 primarily bound to retinoic acid receptors (RARs) and exerted the anti-angiogenic effects by targeting ECs and pericytes via affecting the activation of Wnt/β-catenin and PDGF/PDGFR/PI3K/Akt signaling. Taken together, this study reports a novel retinoic acid drug, EYE-502, which can exert the anti-angiogenic effects by simultaneous targeting of ECs and pericytes.

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“…Chen et al found that sulfarotene could overcome stemness and thus contribute to metastasis or relapse elimination [ 22 ]. In terms of mechanism, sulfarotene interacts with retinoic acid receptors (RARs) and has been found to inhibit the SOS2 pathway, WNT pathway, or regulate epigenetic modifications in various malignancies [ 21 , 40 , 41 ]. Its molecular mechanisms in CRC or TME still need detailed interpretation.…”

Section: Discussionmentioning

confidence: 99%

Sulfarotene Inhibits Colorectal Cancer via Mitigating Natural-Killer-Cell-Induced Stemness

Hu,

Dong,

Zhang

et al. 2024

Pharmaceuticals

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Tumor cell stemness stands out as a pivotal factor driving tumor recurrence or metastasis and significantly contributes to the mortality of patients with colorectal cancer (CRC). Recent research has unveiled a link between immune-active cells and the induction of tumor cell stemness, ultimately leading to heightened resistance to treatment. In this study, stemness in CRC cell lines was assessed after co-culture with natural killer (NK) cells, both with and without sulfarotene administration. Furthermore, a CRC xenograft model was utilized to scrutinize the in vivo efficacy of sulfarotene in overcoming stemness induced by NK cell activation. As a result, CRC cells exhibited significant stemness after NK cell co-culture, as evidenced by the upregulation of several stemness markers associated with cancer stem cells. Moreover, these cells demonstrated remarkable resistance to commonly used chemotherapy agents for CRC, such as oxaliplatin and irinotecan. Importantly, sulfarotene effectively reversed the altered stemness of CRC cells in both in vitro and in vivo assays. In conclusion, sulfarotene emerges as a promising therapeutic strategy for overcoming colorectal cancer resistance to NK cells by effectively inhibiting stemness remodeling. This study underscores the potential of sulfarotene in augmenting NK-cell-mediated immune surveillance, proposing a novel immunotherapeutic approach against colorectal cancer.

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Synthetic Retinoid Kills Drug‐Resistant Cancer Stem Cells via Inducing RARγ‐Translocation‐Mediated Tension Reduction and Chromatin Decondensation

Cited by 6 publications

References 54 publications

Mechanomemory in protein diffusivity of chromatin and nucleoplasm after force cessation

Mechanomemory in protein diffusivity of chromatin and nucleoplasm after force cessation

A novel retinoic acid drug, EYE-502, inhibits choroidal neovascularization by targeting endothelial cells and pericytes

Sulfarotene Inhibits Colorectal Cancer via Mitigating Natural-Killer-Cell-Induced Stemness

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