A novel small-molecule activator of unfolded protein response suppresses castration-resistant prostate cancer growth

Huang, Chen; Miao, Ying; Bian, Aiwu; Ye, Jiangnan; Wang, Jing; Cong, Xiaonan; Jian, Shuyi; Yi, Zhengfang; Liang, Lin; Sun, Zhenliang; Yang, Fan; Ding, Tao

doi:10.1016/j.canlet.2022.215580

Cited by 5 publications

(3 citation statements)

References 61 publications

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“…Irrespective of negative or positive regulation by androgens, the CALR gene must be highly expressed in the activated PP cells and in the antler growth center cells as these proliferating cells require high levels of CALR for maintenance of Ca 2+ homeostasis and prevention of apoptosis. Given that active cells demand increased protein synthesis ( Feng et al, 2015 ), enhanced endoplasmic reticulum activity, such as the unfolded protein response (UPR), is required to facilitate protein folding and protect the cell from deleterious accumulation of unfolded proteins ( Luo and Lee, 2013 ; Chen et al, 2022 ). As an endoplasmic reticulum resident protein, CALR is a well-established effector of the UPR ( Schardt et al, 2011 ; Halperin et al, 2014 ), so the increased expression of CALR in activated PP cells may play a role in facilitating protein correct folding by mediating the UPR.…”

Section: Discussionmentioning

confidence: 99%

Calreticulin Identified as One of the Androgen Response Genes That Trigger Full Regeneration of the Only Capable Mammalian Organ, the Deer Antler

Guo

Zheng

Ba³

et al. 2022

Front. Cell Dev. Biol.

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Deer antlers are male secondary sexual characters that develop to become bone; they are unique appendages that, once lost, can fully regenerate from the permanent bony protuberances or pedicles. Pedicle periosteum (PP) is the tissue that gives rise to the regenerating antlers with three differentiation stages, namely, dormant (DoPP), potentiated (PoPP), and activated (AcPP). Thus far, the transition from the PoPP to the AcPP has not been studied. Our results showed that the AcPP cells maintained their original stem cell features by expressing mesenchymal stem cell (MSC) markers CD73, CD90, and CD105, although they had entered the proliferation mode. The differentially expressed genes (DEGs) in the AcPP compared with those of the PoPP were mainly involved in protein processing, cell cycle, and calcium signaling pathways. Calreticulin (CALR), an androgen response gene, was significantly differentially upregulated in the AcPP cells, and its expression level was negatively regulated by androgens, in contrast to the currently known model systems where all regulation is positive. The downregulation of CALR expression in the AcPP cells in vitro inhibited cell proliferation, induced apoptosis, and inhibited cell cycle progression at G1-S transition. Therefore, CALR is likely a downstream mediator of androgen hormones for triggering initiation of antler regeneration. We believe that the identification of CALR has not only discovered “one critical piece” of the “jigsaw puzzle” in the initiation of antler regeneration but also helps in revealing the mechanism underlying this unique mammalian epimorphic regeneration and has also opened a new avenue for the study of the nature of CALR regulation by androgen (putative binding partners), thus facilitating the identification of potential molecule(s) for investigation as targets for clinical evaluation.

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Section: Discussionmentioning

confidence: 99%

Calreticulin Identified as One of the Androgen Response Genes That Trigger Full Regeneration of the Only Capable Mammalian Organ, the Deer Antler

Guo

Zheng

Ba³

et al. 2022

Front. Cell Dev. Biol.

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“…WJ-644A, a quaternary ammonium salt of the isoquinoline alkaloid class, is reported as an activator of unfolded protein response(UPR). 66 The research groups of Sun, Yang and Ding determined that WJ-644A can induce methuosis in castration-resistant prostate cancer (PC3) and its mouse model, but has it low toxicity to normal cells (RWPE-1, L02) and cannot cause cytoplasmic vacuolization of normal cells. Mechanistically, this study has clearly confirmed that WJ-644A induces methuosis by activating the UPR.…”

Section: Small Molecule Methuosis Inducersmentioning

confidence: 99%

Progress in the discovery and development of small molecule methuosis inducers

Shan

Zhang

2023

RSC Med. Chem.

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“…[ 4 ] Numerous mechanisms can contribute to or promote MDR: The transmembrane P‐glycoprotein (P‐gp) pumps have upregulated expression and are one critical mechanism. [ 5,6 ] P‐gp is encoded by the ATP‐binding cassette (ABC) transporter family ABCB1 gene; [ 7,8 ] P‐gp acquires energy by hydrolyzing ATP to enhance drug efflux in reverse concentrations, thus resulting in a sharp decrease in intracellular medication accumulation. Drug levels fail to reach the therapeutic threshold and eventually lead to MDR.…”

Section: Introductionmentioning

confidence: 99%

Multimodal Nanoplatform with ROS Amplification to Overcome Multidrug Resistance in Prostate Cancer via Targeting P‐Glycoprotein and Ferroptosis

Guan,

Lei,

Xing

et al. 2023

Adv Healthcare Materials

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Chemotherapy remains the most essential treatment for prostate cancer, but multidrug resistance (MDR) contributes to chemotherapy failure and tumor‐related deaths. The overexpression of P‐glycoprotein (P‐gp) is one of the main mechanisms behind MDR. Here, we report a multimodal nanoplatform with a reactive oxygen species (ROS) cascade for gas therapy/ferroptosis/chemotherapy in reversing MDR. The nanoplatform disassembles when responding to intracellular ROS and exerts three main functions: First, NO‐targeted delivery could reverse MDR by downregulating P‐gp expression and inhibiting mitochondrial function. Second, ferrocene‐induced ferroptosis breaks the redox balance in the tumor intracellular microenvironment and synergistically acts against the tumor. Third, the release of paclitaxel is precisely controlled in situ in the tumor for chemotherapy that avoids damage to normal tissues. Excitingly, this multimodal nanoplatform is a promising weapon for reversing MDR and may provide a pioneering paradigm for synergetic cancer therapy.This article is protected by copyright. All rights reserved

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A novel small-molecule activator of unfolded protein response suppresses castration-resistant prostate cancer growth

Cited by 5 publications

References 61 publications

Calreticulin Identified as One of the Androgen Response Genes That Trigger Full Regeneration of the Only Capable Mammalian Organ, the Deer Antler

Calreticulin Identified as One of the Androgen Response Genes That Trigger Full Regeneration of the Only Capable Mammalian Organ, the Deer Antler

Progress in the discovery and development of small molecule methuosis inducers

Multimodal Nanoplatform with ROS Amplification to Overcome Multidrug Resistance in Prostate Cancer via Targeting P‐Glycoprotein and Ferroptosis

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