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This article is reproduced from the WeChat public account of "Dingxiang Academic".
Liver cancer is the fourth most fatal malignant tumor worldwide, and hepatocellular carcinoma is the most important type of tissue, and treatment is extremely difficult.
In recent years, although the treatment of hepatocellular carcinoma has gradually emerged, it still faces severe challenges.
One of the dawns comes from targeted drugs.
Many studies have found that targeted drugs can significantly prolong the survival period of patients with hepatocellular carcinoma, but drug resistance is prone to exist in the clinical application of targeted drugs.
Resistance is one of the serious challenges.
Sorafenib is the first clinically targeted drug used in the treatment of liver cancer.
It has the longest clinical application time and the most extensive experience.
At the same time, it is also the most widely studied targeted drug that has the most drug resistance.
Its development and maintenance of drug resistance The mechanism is complicated.
People have long discovered that there is a special abnormal metabolic pattern in the process of tumor formation, which is called Weinberger's phenomenon.
In recent years, studies have shown that metabolic reprogramming plays an important role in tumor response to drug treatment, and intracellular redox balance is an important part of metabolism.
Whether it is involved in the formation of sorafenib resistance is unknown.
Important issues.
A research team led by Professor Cai Xiujun from the Run Run Run Run Run Run Hospital of Zhejiang University School of Medicine recently discovered that redox metabolism can reshape the drug response of hepatocellular carcinoma to sorafenib, which is one of the important links in the formation of drug resistance.
The study revealed the mechanism of liver cancer targeted therapy resistance from the perspective of mitochondrial metabolism, and was published in the Journal of Signal Transduction and Targeted Therapy (IF=13.
493) in the form of a cover highlight. Previous studies have found that sorafenib can increase intracellular ROS levels and induce apoptosis by acting on mitochondrial ETC complexes, suggesting that drug-resistant cells must first overcome the increase in intracellular ROS levels.
In this study, the research team found that under the same concentration of sorafenib treatment, the level of ROS in drug-resistant cells was significantly lower than that in wild-type cells, which supports the regulation of intracellular ROS balance involved in the development of sorafenib resistance Conjecture.
Since mitochondria are an important source of ROS in cells, the research team further explored the role of mitochondria in it.
Through the observation of mitochondrial function and morphology, it is found that the mitochondrial morphology in drug-resistant cells is more complete than that of wild cells, but the number of mitochondria is significantly reduced.
The research team speculates whether it is the increased level of mitochondrial autophagy in drug-resistant cells, leading to a decrease in the number of mitochondria and maintaining mitochondrial homeostasis, thereby participating in the process of drug resistance? However, follow-up research results suggest that the level of mitochondrial autophagy in drug-resistant cells is lower than that in wild-type cells.
Therefore, the research team further speculated whether the above performance is caused by the decrease of mitochondrial production in drug-resistant cells? By detecting the expression levels of key proteins produced by mitochondria (PGC1α and PGC1β), the research team found that PGC1β protein levels were significantly reduced in drug-resistant cells.
Overexpression of PGC1β protein levels in drug-resistant cells can significantly increase intracellular ROS levels.
The above results suggest that the reduced level of PGC1β protein can reduce mitochondrial synthesis, thereby reducing the cellular stress of cells treated with sorafenib and reducing the production of intracellular ROS.
Further research found that the ubiquitin-protease system is involved in the regulation of PGC1β protein level and is regulated by the protein UBQLN1.
UBQLN1 participates in the regulation of intracellular ubiquitination degradation process, and plays an important role in neurodegenerative diseases and tumors.
UBQLN1 has diverse functions and participates in the above process through a variety of mechanisms: UBQLN1 can bind to ubiquitinated proteins and promote the degradation of the latter through the proteasome pathway; UBQLN1 can also increase the level of ubiquitination on proteins.
More studies have found that UBQLN1 can even stabilize certain proteins with special structures.
In this study, the research team found that UBQLN1 can promote PGC1β protein degradation in cells, thereby participating in the occurrence of sorafenib resistance.
Importantly, this study found that the up-regulated UBQLN1 in drug-resistant cells can mediate PGC1β ubiquitination-independent protein degradation, thereby remodeling mitochondria and redox metabolism, suggesting that further modification of UBQLN1 is expected to develop a PROTAC-like Novel targeted protein degradation strategy.
In summary, the research team found that the level of mitochondrial biosynthesis was reduced when sorafenib was resistant to liver cancer, thereby maintaining a low pressure of reactive oxygen radicals in tumor cells and helping tumor cells in the targeted therapy of sorafenib.
Survive better, reveal the internal environmental mechanism of liver cancer targeted therapy resistance from the perspective of tumor energy metabolism and redox reprogramming, and provide new ideas and new basis for the development of new therapeutic strategies and the monitoring of targeted therapy efficacy.
Strong prospect and value of clinical transformation.
Professor Cai Xiujun is the corresponding author of the paper, and Xu Junjie is the first author of the paper.
This research was funded by major national scientific research projects, the National Natural Science Foundation of China, the Zhejiang Provincial Key R&D Program, and the China Postdoctoral Science Foundation.
End's previous selection of onlookers Cell Breakthrough: The foodies are moved and cry! Scientists have found a new fat-burning pathway with the potential for long-lasting effect.
Finally! Sinopharm officially announced the Phase 3 clinical data of two new crown inactivated vaccines, both of which are more than 70% effective in preventing COVID-19.
Scientists from Peking University publish the top issue of Cell: Using spliceosome inhibitors to produce all-round stem cells in mice.
The world's "popular fried chicken"! New research reveals: Nicotinamide can also regulate retinal function, effectively improve glaucoma craze and write a new legend in gene therapy.
Optogenetic therapy has revived blind people who have been blind for 40 years for the first time.
Medical immunotherapy| Biosimilars| Vaccines| Drug resistance| Drug Targets| Healthy Life| Pharmaceutical News| Drug Inventory| Pharmaceutical Technology| Basic Research on Drug Side Effects/ Translational Medicine Leukemia| Lung Cancer| Gastric Cancer| Colorectal Cancer| Liver Cancer| Breast Cancer| Pancreatic Cancer| Cardiovascular Disease| Neurodegenerative Diseases | Intestinal microbial medical devices/biotechnological in vitro diagnostics | Medical devices | Bio-nano | 3D printing | Genetic testing | Single cell sequencing | Gene editing | Assisted reproduction | Artificial intelligence | Precision medicine policy anti-cancer drugs | 4+7 volume procurement | Consumables | Filing System | Registrant System | Healthy China | New Edition of Essential Medicines Directory | AI Medical Devices | Telemedicine | Same Equity Different Equity Market/Capital IPO | Financing | Cooperation | Funds | Hong Kong Stock Exchange | Science and Technology Innovation Board | ChiNext | R&D Investment | Acquisitions | Market & Consumption
Liver cancer is the fourth most fatal malignant tumor worldwide, and hepatocellular carcinoma is the most important type of tissue, and treatment is extremely difficult.
In recent years, although the treatment of hepatocellular carcinoma has gradually emerged, it still faces severe challenges.
One of the dawns comes from targeted drugs.
Many studies have found that targeted drugs can significantly prolong the survival period of patients with hepatocellular carcinoma, but drug resistance is prone to exist in the clinical application of targeted drugs.
Resistance is one of the serious challenges.
Sorafenib is the first clinically targeted drug used in the treatment of liver cancer.
It has the longest clinical application time and the most extensive experience.
At the same time, it is also the most widely studied targeted drug that has the most drug resistance.
Its development and maintenance of drug resistance The mechanism is complicated.
People have long discovered that there is a special abnormal metabolic pattern in the process of tumor formation, which is called Weinberger's phenomenon.
In recent years, studies have shown that metabolic reprogramming plays an important role in tumor response to drug treatment, and intracellular redox balance is an important part of metabolism.
Whether it is involved in the formation of sorafenib resistance is unknown.
Important issues.
A research team led by Professor Cai Xiujun from the Run Run Run Run Run Run Hospital of Zhejiang University School of Medicine recently discovered that redox metabolism can reshape the drug response of hepatocellular carcinoma to sorafenib, which is one of the important links in the formation of drug resistance.
The study revealed the mechanism of liver cancer targeted therapy resistance from the perspective of mitochondrial metabolism, and was published in the Journal of Signal Transduction and Targeted Therapy (IF=13.
493) in the form of a cover highlight. Previous studies have found that sorafenib can increase intracellular ROS levels and induce apoptosis by acting on mitochondrial ETC complexes, suggesting that drug-resistant cells must first overcome the increase in intracellular ROS levels.
In this study, the research team found that under the same concentration of sorafenib treatment, the level of ROS in drug-resistant cells was significantly lower than that in wild-type cells, which supports the regulation of intracellular ROS balance involved in the development of sorafenib resistance Conjecture.
Since mitochondria are an important source of ROS in cells, the research team further explored the role of mitochondria in it.
Through the observation of mitochondrial function and morphology, it is found that the mitochondrial morphology in drug-resistant cells is more complete than that of wild cells, but the number of mitochondria is significantly reduced.
The research team speculates whether it is the increased level of mitochondrial autophagy in drug-resistant cells, leading to a decrease in the number of mitochondria and maintaining mitochondrial homeostasis, thereby participating in the process of drug resistance? However, follow-up research results suggest that the level of mitochondrial autophagy in drug-resistant cells is lower than that in wild-type cells.
Therefore, the research team further speculated whether the above performance is caused by the decrease of mitochondrial production in drug-resistant cells? By detecting the expression levels of key proteins produced by mitochondria (PGC1α and PGC1β), the research team found that PGC1β protein levels were significantly reduced in drug-resistant cells.
Overexpression of PGC1β protein levels in drug-resistant cells can significantly increase intracellular ROS levels.
The above results suggest that the reduced level of PGC1β protein can reduce mitochondrial synthesis, thereby reducing the cellular stress of cells treated with sorafenib and reducing the production of intracellular ROS.
Further research found that the ubiquitin-protease system is involved in the regulation of PGC1β protein level and is regulated by the protein UBQLN1.
UBQLN1 participates in the regulation of intracellular ubiquitination degradation process, and plays an important role in neurodegenerative diseases and tumors.
UBQLN1 has diverse functions and participates in the above process through a variety of mechanisms: UBQLN1 can bind to ubiquitinated proteins and promote the degradation of the latter through the proteasome pathway; UBQLN1 can also increase the level of ubiquitination on proteins.
More studies have found that UBQLN1 can even stabilize certain proteins with special structures.
In this study, the research team found that UBQLN1 can promote PGC1β protein degradation in cells, thereby participating in the occurrence of sorafenib resistance.
Importantly, this study found that the up-regulated UBQLN1 in drug-resistant cells can mediate PGC1β ubiquitination-independent protein degradation, thereby remodeling mitochondria and redox metabolism, suggesting that further modification of UBQLN1 is expected to develop a PROTAC-like Novel targeted protein degradation strategy.
In summary, the research team found that the level of mitochondrial biosynthesis was reduced when sorafenib was resistant to liver cancer, thereby maintaining a low pressure of reactive oxygen radicals in tumor cells and helping tumor cells in the targeted therapy of sorafenib.
Survive better, reveal the internal environmental mechanism of liver cancer targeted therapy resistance from the perspective of tumor energy metabolism and redox reprogramming, and provide new ideas and new basis for the development of new therapeutic strategies and the monitoring of targeted therapy efficacy.
Strong prospect and value of clinical transformation.
Professor Cai Xiujun is the corresponding author of the paper, and Xu Junjie is the first author of the paper.
This research was funded by major national scientific research projects, the National Natural Science Foundation of China, the Zhejiang Provincial Key R&D Program, and the China Postdoctoral Science Foundation.
End's previous selection of onlookers Cell Breakthrough: The foodies are moved and cry! Scientists have found a new fat-burning pathway with the potential for long-lasting effect.
Finally! Sinopharm officially announced the Phase 3 clinical data of two new crown inactivated vaccines, both of which are more than 70% effective in preventing COVID-19.
Scientists from Peking University publish the top issue of Cell: Using spliceosome inhibitors to produce all-round stem cells in mice.
The world's "popular fried chicken"! New research reveals: Nicotinamide can also regulate retinal function, effectively improve glaucoma craze and write a new legend in gene therapy.
Optogenetic therapy has revived blind people who have been blind for 40 years for the first time.
Medical immunotherapy| Biosimilars| Vaccines| Drug resistance| Drug Targets| Healthy Life| Pharmaceutical News| Drug Inventory| Pharmaceutical Technology| Basic Research on Drug Side Effects/ Translational Medicine Leukemia| Lung Cancer| Gastric Cancer| Colorectal Cancer| Liver Cancer| Breast Cancer| Pancreatic Cancer| Cardiovascular Disease| Neurodegenerative Diseases | Intestinal microbial medical devices/biotechnological in vitro diagnostics | Medical devices | Bio-nano | 3D printing | Genetic testing | Single cell sequencing | Gene editing | Assisted reproduction | Artificial intelligence | Precision medicine policy anti-cancer drugs | 4+7 volume procurement | Consumables | Filing System | Registrant System | Healthy China | New Edition of Essential Medicines Directory | AI Medical Devices | Telemedicine | Same Equity Different Equity Market/Capital IPO | Financing | Cooperation | Funds | Hong Kong Stock Exchange | Science and Technology Innovation Board | ChiNext | R&D Investment | Acquisitions | Market & Consumption
