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Editor's note iNature is China's largest academic public account.
It is jointly created by doctoral teams from Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature talent public account is now launched, focusing on talent recruitment, academic progress, and scientific research information.
Long press or scan the QR code below to follow us
.
iNature hepatocellular carcinoma (HCC) is one of the most common forms of cancer and is associated with poor patient prognosis
.
To date, the emergence of therapeutic resistance has hindered the efficacy of targeted therapies for the treatment of HCC patients
.
On January 4, 2022, Liang Jun of Peking University, Lou Jizhong and Song Guangtao of the Institute of Biophysics of the Chinese Academy of Sciences jointly published an online article entitled "CRISPR screens uncover protective effect of PSTK as a regulator of chemotherapy-induced chemotherapy in Molecular Cancer (IF=27).
ferroptosis in hepatocellular carcinoma", which found that inhibition of phosphoseryl tRNA kinase (PSTK) increases the sensitivity of HCC cells to chemotherapy
.
PSTK is associated with inhibition of chemotherapy-induced ferroptosis in HCC cells, depletion of PSTK leads to inactivation of glutathione peroxide 4 (GPX4) and glutathione due to inhibition of selenocysteine and cysteine synthesis Disruption of glutathione (GSH) metabolism, thereby enhancing the induction of ferroptosis following targeted chemotherapy treatment
.
Punicalin, a drug for the treatment of hepatitis B virus (HBV), was identified as a possible PSTK inhibitor that exhibited synergistic effects when used with sorafenib in the treatment of HCC in vitro and in vivo
.
Taken together, these results highlight PSTK as a key mediator of resistance to targeted therapy in HCC cells by inhibiting ferroptosis induction
.
Therefore, PSTK inhibitors may be ideal candidates for overcoming drug resistance in HCC
.
Hepatocellular carcinoma (HCC) is a highly lethal cancer that is increasingly emerging worldwide
.
Sorafenib is the first multikinase inhibitor approved for patients with advanced HCC
.
However, the objective response rate (ORR) to sorafenib in HCC patients is less than 10%, and the inhibitor does not prevent the progression of advanced HCC due to the emergence of resistance
.
The development of HCC tumors is associated with the progressive acquisition of mutations in genes encoding many cell cycle-related proteins
.
Historically, small-molecule drugs targeting cyclin-dependent kinases (CDKs) have been used to inhibit the development of such tumors
.
For example, Palbociclib (PD0332991), a specific CDK4/6 inhibitor developed by Pfizer, has shown activity in patients with advanced HCC after failure on a single line of rafenib
.
Further understanding of the mechanisms that control the resistance of HCC tumor cells to these targeted therapy drugs is critical to guide further efforts to sensitize HCC cells to these potent drugs
.
Schematic diagram of the article (picture from Molecular Cancer) Ferroptosis is a form of programmed cell death that differs from necrosis, apoptosis and autophagy in related genetic processes, biochemical activities and morphological features
.
Ferroptosis is characterized by the accumulation of lipid peroxidation products and oxidized phospholipids in an iron-dependent manner
.
Because cancer cells utilize higher levels of iron than normal cells to fuel their more aggressive growth, tumors are more sensitive to ferroptosis-inducing agents
.
Therefore, such ferroptosis inducers have been proposed as promising tools for the treatment of drug-resistant tumors, especially in HCC
.
Therefore, efforts to increase the susceptibility of HCC cells to ferroptosis are expected to sensitize these cells to sorafenib
.
CRISPR/Cas9 is a powerful gene editing technology that has been used to perform an increasing number of high-throughput screens
.
CRISPR/Cas9-based library screening systems can be used to identify genes whose repression increases or decreases the efficacy of anticancer drugs
.
Several CRISPR/Cas9 screens have been performed to identify novel HCC targets
.
To extend these analyses, the study here performed a series of CRISPR/Cas9 knockdowns using HCC cells treated with tyrosine kinase inhibitors (TKIs), CDK4/6 inhibitors, or Erastin, a canonical inducer of ferroptosis.
Except filtering
.
Using this approach, the study identified phosphoseryl tRNA kinase (PSTK), an essential RNA-dependent kinase, as a key mediator of HCC cell resistance to targeted therapy
.
PSTK is a key mediator of selenocysteine biosynthesis, forming the active center of selenoproteins
.
Our data confirm the important role of PSTK in regulating ferroptosis-related chemoresistance in HCC cells
.
Specifically, this study found that PSTK was able to prevent ferroptosis induction by maintaining glutathione peroxidase 4 (GPX4) activity and promoting glutathione (GSH) metabolism and folate biosynthesis
.
Thus, our findings suggest that targeting PSTK may represent a viable approach to overcome chemoresistance in HCC by inducing ferroptosis
.
Reference message: https://molecular-cancer.
biomedcentral.
com/articles/10.
1186/s12943-021-01466-9
It is jointly created by doctoral teams from Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature talent public account is now launched, focusing on talent recruitment, academic progress, and scientific research information.
Long press or scan the QR code below to follow us
.
iNature hepatocellular carcinoma (HCC) is one of the most common forms of cancer and is associated with poor patient prognosis
.
To date, the emergence of therapeutic resistance has hindered the efficacy of targeted therapies for the treatment of HCC patients
.
On January 4, 2022, Liang Jun of Peking University, Lou Jizhong and Song Guangtao of the Institute of Biophysics of the Chinese Academy of Sciences jointly published an online article entitled "CRISPR screens uncover protective effect of PSTK as a regulator of chemotherapy-induced chemotherapy in Molecular Cancer (IF=27).
ferroptosis in hepatocellular carcinoma", which found that inhibition of phosphoseryl tRNA kinase (PSTK) increases the sensitivity of HCC cells to chemotherapy
.
PSTK is associated with inhibition of chemotherapy-induced ferroptosis in HCC cells, depletion of PSTK leads to inactivation of glutathione peroxide 4 (GPX4) and glutathione due to inhibition of selenocysteine and cysteine synthesis Disruption of glutathione (GSH) metabolism, thereby enhancing the induction of ferroptosis following targeted chemotherapy treatment
.
Punicalin, a drug for the treatment of hepatitis B virus (HBV), was identified as a possible PSTK inhibitor that exhibited synergistic effects when used with sorafenib in the treatment of HCC in vitro and in vivo
.
Taken together, these results highlight PSTK as a key mediator of resistance to targeted therapy in HCC cells by inhibiting ferroptosis induction
.
Therefore, PSTK inhibitors may be ideal candidates for overcoming drug resistance in HCC
.
Hepatocellular carcinoma (HCC) is a highly lethal cancer that is increasingly emerging worldwide
.
Sorafenib is the first multikinase inhibitor approved for patients with advanced HCC
.
However, the objective response rate (ORR) to sorafenib in HCC patients is less than 10%, and the inhibitor does not prevent the progression of advanced HCC due to the emergence of resistance
.
The development of HCC tumors is associated with the progressive acquisition of mutations in genes encoding many cell cycle-related proteins
.
Historically, small-molecule drugs targeting cyclin-dependent kinases (CDKs) have been used to inhibit the development of such tumors
.
For example, Palbociclib (PD0332991), a specific CDK4/6 inhibitor developed by Pfizer, has shown activity in patients with advanced HCC after failure on a single line of rafenib
.
Further understanding of the mechanisms that control the resistance of HCC tumor cells to these targeted therapy drugs is critical to guide further efforts to sensitize HCC cells to these potent drugs
.
Schematic diagram of the article (picture from Molecular Cancer) Ferroptosis is a form of programmed cell death that differs from necrosis, apoptosis and autophagy in related genetic processes, biochemical activities and morphological features
.
Ferroptosis is characterized by the accumulation of lipid peroxidation products and oxidized phospholipids in an iron-dependent manner
.
Because cancer cells utilize higher levels of iron than normal cells to fuel their more aggressive growth, tumors are more sensitive to ferroptosis-inducing agents
.
Therefore, such ferroptosis inducers have been proposed as promising tools for the treatment of drug-resistant tumors, especially in HCC
.
Therefore, efforts to increase the susceptibility of HCC cells to ferroptosis are expected to sensitize these cells to sorafenib
.
CRISPR/Cas9 is a powerful gene editing technology that has been used to perform an increasing number of high-throughput screens
.
CRISPR/Cas9-based library screening systems can be used to identify genes whose repression increases or decreases the efficacy of anticancer drugs
.
Several CRISPR/Cas9 screens have been performed to identify novel HCC targets
.
To extend these analyses, the study here performed a series of CRISPR/Cas9 knockdowns using HCC cells treated with tyrosine kinase inhibitors (TKIs), CDK4/6 inhibitors, or Erastin, a canonical inducer of ferroptosis.
Except filtering
.
Using this approach, the study identified phosphoseryl tRNA kinase (PSTK), an essential RNA-dependent kinase, as a key mediator of HCC cell resistance to targeted therapy
.
PSTK is a key mediator of selenocysteine biosynthesis, forming the active center of selenoproteins
.
Our data confirm the important role of PSTK in regulating ferroptosis-related chemoresistance in HCC cells
.
Specifically, this study found that PSTK was able to prevent ferroptosis induction by maintaining glutathione peroxidase 4 (GPX4) activity and promoting glutathione (GSH) metabolism and folate biosynthesis
.
Thus, our findings suggest that targeting PSTK may represent a viable approach to overcome chemoresistance in HCC by inducing ferroptosis
.
Reference message: https://molecular-cancer.
biomedcentral.
com/articles/10.
1186/s12943-021-01466-9
