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Editor’s note iNature is China’s largest academic official account.
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNature Multidrug Resistance (MDR) remains a major challenge for successful cancer treatment
.
Many mechanisms that confer treatment-induced resistance have been extensively studied to explore how to combat MDR
.
In this regard, lysosomal sequestration has been shown to be a mechanism that leads to drug resistance through an "off-target" effect, in which hydrophobic and weakly alkaline chemotherapeutics are trapped in the lysosome, isolating them from the target
.
Methods to disrupt lysosomal acidification, regulate acid sphingomyelinase (ASM) and increase lysosomal membrane permeability have been developed to overcome drug resistance
.
On June 7, 2021, Hongxiang Lou and Huiqing Yuan of Shandong University jointly published an online report entitled "Targeting of VPS18 by the lysosomotropic agent RDN reverses TFE3-mediated drug resistance" on Signal Transduction and Targeted Therapy (IF=13.
49).
Research paper, this study proved the new function of TFE3/lysosome/MRP2 in the development of MDR through the lysosomal isolation mechanism
.
The contribution of lysosomal VPS18 to the development of cancer and drug resistance can be explored as a potential therapeutic target.
It is specifically inhibited by a new compound RDN to treat acquired drug-resistant cancer
.
Multidrug resistance (MDR) remains a major challenge for successful cancer treatment
.
Many mechanisms that confer treatment-induced resistance have been extensively studied to explore how to combat MDR
.
In this regard, lysosomal isolation has been shown to be a mechanism that leads to drug resistance through an "off-target" effect, in which hydrophobic and weakly alkaline chemotherapeutics are trapped in the lysosome, isolating them from the target
.
Methods to disrupt lysosomal acidification, regulate acid sphingomyelinase (ASM) and increase lysosomal membrane permeability have been developed to overcome drug resistance
.
Transcription factor E3 (TFE3) and TFEB become the main regulators of lysosomal biogenesis and autophagy in response to cellular stress.
Therefore, interruption of TFE3/TFEB-mediated effects has great therapeutic potential in cancer
.
In this study, a new mechanism was revealed by which TFE3/lysosomes activate the response to therapeutic agents, such as docetaxel (Doc), by promoting the dissolution of multidrug resistance-related protein 2 (MRP2).
Enzyme positioning and enhancing drug sequestration in the lysosome to promote MDR.
The study also identified lysosomal vacuolar protein sorting 18 (VPS18) as a new type of lysosomal drug RDN (a natural double benzyl riccardin).
D's aminomethylated derivatives) are potential targets for the reversal of chemoresistance
.
The study initially evaluated the changes in gene expression in Doc-induced multidrug resistance PC3/Doc cancer cells
.
The expression profile of genes related to lysosomal and mitochondrial pathway metabolism is particularly altered in resistant cells
.
The examination of lysosome-related parameters showed that the number of lysosomes and autophagosomes increased significantly in different resistant cell lines
.
Therefore, lysosomal activation is the result of different anti-tumor drug treatments
.
Given the importance of TFEB and TFE3 in regulating lysosomal biogenesis, this study determined the involvement of these two factors in the treatment-induced metabolic transformation to lysosomes
.
The results clearly show that clinical drugs significantly activate TFEB and TFE3, especially TFE3, and promote TFE3 nuclear translocation (a highly phosphorylated active form) in vitro and in vivo
.
Next, it was determined whether the treatment-activated TFE3/lysosome contributes to resistance
.
Down-regulation of TFE3 significantly restored the sensitivity of PC3/Doc cells to Doc or Dox, while overexpression of TFE3 significantly increased the tolerance of PC3 cells to drugs, indicating the role of TFE3 in conferring MDR
.
Therefore, lysosomal-mediated capture of Doc or Dox can cause off-target effects, thereby reducing its anti-tumor efficacy
.
To explore the underlying mechanism of lysosomal drug sequestration, this study tested whether the ABC family of transporters act as cell membrane pumps and play a key role in mediating MDR
.
The screening assay identified MRP2 (ABCC2) as an important mediator of lysosomal resistance
.
Although MRP2 is mainly located on the cell membrane, a large amount of MRP2 is present in the cytoplasm and appears to be colocalized with lysosomal-associated membrane protein 2 (LAMP2) in resistant cells
.
Further studies have determined that MRP2 is the target of TFE3, which can enhance the expression of MRP2 through the transcription of the E-box motif in the MRP2 promoter after chemical treatment
.
Therefore, treatment-driven activation of TFE3 stimulates the expression and localization of MRP2 in lysosomes, and promotes lysosomal-mediated drug capture and drug resistance
.
Schematic diagram of the article (picture from STTT) The study next determined whether targeting the TFE3/lysosome axis is effective in reversing MDR
.
The results indicate that RDN binds to the RING domain of VPS18, leading to the destruction of the VPS-C core complex and lysosome function
.
In order to explore whether VPS18 is an important pathological effector, the study first detected the level of VPS18 in cancer
.
The results showed that the expression of VPS18 in several cancers was higher than that of adjacent non-cancerous tissues, including prostate cancer (PRAD), bladder cancer (BLCA), liver cancer (LIHC) and lung cancer (LUAD)
.
High levels of VPS18 are associated with poor prognosis of malignant cancer
.
VPS18 knockdown significantly inhibited cancer cell proliferation and tumor growth in mice
.
Importantly, the study observed that VPS18 expression can be induced by different chemotherapeutic drugs and increased significantly in drug-resistant cells
.
VPS18 silencing significantly increased the sensitivity of drug-resistant cells to Doc and Dox, while overexpression of VPS18 inhibited the effect of chemotherapy drugs on cell proliferation
.
Therefore, VPS18 has become a new molecular indicator of tumor prognosis and a target for reversing lysosomal-mediated drug resistance
.
In conclusion, the evidence provided by this study proves the new function of TFE3/lysosome/MRP2 in the development of MDR through the lysosomal sequestration mechanism
.
The contribution of lysosomal VPS18 to the development of cancer and drug resistance can be explored as a potential therapeutic target.
It is specifically inhibited by a new compound RDN to treat acquired drug-resistant cancer
.
Reference message: https://
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNature Multidrug Resistance (MDR) remains a major challenge for successful cancer treatment
.
Many mechanisms that confer treatment-induced resistance have been extensively studied to explore how to combat MDR
.
In this regard, lysosomal sequestration has been shown to be a mechanism that leads to drug resistance through an "off-target" effect, in which hydrophobic and weakly alkaline chemotherapeutics are trapped in the lysosome, isolating them from the target
.
Methods to disrupt lysosomal acidification, regulate acid sphingomyelinase (ASM) and increase lysosomal membrane permeability have been developed to overcome drug resistance
.
On June 7, 2021, Hongxiang Lou and Huiqing Yuan of Shandong University jointly published an online report entitled "Targeting of VPS18 by the lysosomotropic agent RDN reverses TFE3-mediated drug resistance" on Signal Transduction and Targeted Therapy (IF=13.
49).
Research paper, this study proved the new function of TFE3/lysosome/MRP2 in the development of MDR through the lysosomal isolation mechanism
.
The contribution of lysosomal VPS18 to the development of cancer and drug resistance can be explored as a potential therapeutic target.
It is specifically inhibited by a new compound RDN to treat acquired drug-resistant cancer
.
Multidrug resistance (MDR) remains a major challenge for successful cancer treatment
.
Many mechanisms that confer treatment-induced resistance have been extensively studied to explore how to combat MDR
.
In this regard, lysosomal isolation has been shown to be a mechanism that leads to drug resistance through an "off-target" effect, in which hydrophobic and weakly alkaline chemotherapeutics are trapped in the lysosome, isolating them from the target
.
Methods to disrupt lysosomal acidification, regulate acid sphingomyelinase (ASM) and increase lysosomal membrane permeability have been developed to overcome drug resistance
.
Transcription factor E3 (TFE3) and TFEB become the main regulators of lysosomal biogenesis and autophagy in response to cellular stress.
Therefore, interruption of TFE3/TFEB-mediated effects has great therapeutic potential in cancer
.
In this study, a new mechanism was revealed by which TFE3/lysosomes activate the response to therapeutic agents, such as docetaxel (Doc), by promoting the dissolution of multidrug resistance-related protein 2 (MRP2).
Enzyme positioning and enhancing drug sequestration in the lysosome to promote MDR.
The study also identified lysosomal vacuolar protein sorting 18 (VPS18) as a new type of lysosomal drug RDN (a natural double benzyl riccardin).
D's aminomethylated derivatives) are potential targets for the reversal of chemoresistance
.
The study initially evaluated the changes in gene expression in Doc-induced multidrug resistance PC3/Doc cancer cells
.
The expression profile of genes related to lysosomal and mitochondrial pathway metabolism is particularly altered in resistant cells
.
The examination of lysosome-related parameters showed that the number of lysosomes and autophagosomes increased significantly in different resistant cell lines
.
Therefore, lysosomal activation is the result of different anti-tumor drug treatments
.
Given the importance of TFEB and TFE3 in regulating lysosomal biogenesis, this study determined the involvement of these two factors in the treatment-induced metabolic transformation to lysosomes
.
The results clearly show that clinical drugs significantly activate TFEB and TFE3, especially TFE3, and promote TFE3 nuclear translocation (a highly phosphorylated active form) in vitro and in vivo
.
Next, it was determined whether the treatment-activated TFE3/lysosome contributes to resistance
.
Down-regulation of TFE3 significantly restored the sensitivity of PC3/Doc cells to Doc or Dox, while overexpression of TFE3 significantly increased the tolerance of PC3 cells to drugs, indicating the role of TFE3 in conferring MDR
.
Therefore, lysosomal-mediated capture of Doc or Dox can cause off-target effects, thereby reducing its anti-tumor efficacy
.
To explore the underlying mechanism of lysosomal drug sequestration, this study tested whether the ABC family of transporters act as cell membrane pumps and play a key role in mediating MDR
.
The screening assay identified MRP2 (ABCC2) as an important mediator of lysosomal resistance
.
Although MRP2 is mainly located on the cell membrane, a large amount of MRP2 is present in the cytoplasm and appears to be colocalized with lysosomal-associated membrane protein 2 (LAMP2) in resistant cells
.
Further studies have determined that MRP2 is the target of TFE3, which can enhance the expression of MRP2 through the transcription of the E-box motif in the MRP2 promoter after chemical treatment
.
Therefore, treatment-driven activation of TFE3 stimulates the expression and localization of MRP2 in lysosomes, and promotes lysosomal-mediated drug capture and drug resistance
.
Schematic diagram of the article (picture from STTT) The study next determined whether targeting the TFE3/lysosome axis is effective in reversing MDR
.
The results indicate that RDN binds to the RING domain of VPS18, leading to the destruction of the VPS-C core complex and lysosome function
.
In order to explore whether VPS18 is an important pathological effector, the study first detected the level of VPS18 in cancer
.
The results showed that the expression of VPS18 in several cancers was higher than that of adjacent non-cancerous tissues, including prostate cancer (PRAD), bladder cancer (BLCA), liver cancer (LIHC) and lung cancer (LUAD)
.
High levels of VPS18 are associated with poor prognosis of malignant cancer
.
VPS18 knockdown significantly inhibited cancer cell proliferation and tumor growth in mice
.
Importantly, the study observed that VPS18 expression can be induced by different chemotherapeutic drugs and increased significantly in drug-resistant cells
.
VPS18 silencing significantly increased the sensitivity of drug-resistant cells to Doc and Dox, while overexpression of VPS18 inhibited the effect of chemotherapy drugs on cell proliferation
.
Therefore, VPS18 has become a new molecular indicator of tumor prognosis and a target for reversing lysosomal-mediated drug resistance
.
In conclusion, the evidence provided by this study proves the new function of TFE3/lysosome/MRP2 in the development of MDR through the lysosomal sequestration mechanism
.
The contribution of lysosomal VPS18 to the development of cancer and drug resistance can be explored as a potential therapeutic target.
It is specifically inhibited by a new compound RDN to treat acquired drug-resistant cancer
.
Reference message: https://
