There is a new solution to the problem of ovarian cancer resistance

is an ovarian cancer patient who was treated at the Oncology Hospital of the Chinese Academy of Medical Sciences. After just over a month of chemotherapy, she developed a severe drug-resistant reaction. Her abdominal and pelvic cavity became hard due to the spread of tumor cells, accompanied by chest tightness, fever, swelling of the lower limbs and other symptoms. Unfortunately, this drug-resistant response is not uncommon and has become a major obstacle to the treatment of ovarian cancer.
Recently, Liu Zhihua, a professor at the National Key Laboratory of Molecular Oncology at the Oncology Hospital of the Chinese Academy of Medical Sciences, discovered a regulatory axis for ovarian cancer resistance and proposed a joint use of two inhibitors to overcome resistance. The results were published in the Proceedings of the National Academy of Sciences, with Wu Xiaoxuan and Luo Jinyu, Ph.D., Oncology Hospital, Chinese Academy of Medical Sciences, as co-authors.ovarian cancer is one of the most common gynaecological malignancies, the five-year survival rate is less than 30%, the highest rate of death in gynaecological tumors. Platinum-based chemotherapy is the main means to maintain the survival of patients, but more patients will appear after surgery and chemotherapy drug resistance, tumor recurrence and metastasis.
once drug resistance occurs, clinical treatment can only retreat to the second, choose dossythase, lipid amycin and other low-effective drug treatment.
to explore the drug-resistant mechanism of ovarian cancer, find effective targets and drugs, improve the sensitivity of ovarian cancer cells to chemotherapy drugs, is of great significance to improve treatment and improve the five-year survival rate of ovarian cancer patients.
chemotherapy resistance is a complex process affected by many factors, in which the apoptosis escape of tumor cells plays a key role. MCL1 is an important member of the family of anti-apoptosis protein BCL-2, which is expressed higher in a variety of malignant tumors, including ovarian cancer, leading to drug resistance.
but because of the special molecular structure of MCL1, there are very few specific inhibitors for it. At present, only one inhibitor is effective in the blood system, and the inhibition effect on solid tumors such as ovarian cancer is not obvious. Therefore, the researchers wanted to find its upstream molecule, by regulating the upstream molecule to achieve the suppression of MCL1.and de-ubibination are both modified types of proteins that promote and inhibit the process of protein degradation, respectively. Because they can regulate the expression of many important cancer genes and anti-cancer genes, they are the focus of cancer research in recent years.
Liu Zhihua's team has a certain research basis for ubibinization and de-ubitinase, and they hope to find a de-ubitinase that can regulate MCL1.
researchers used library screening to explore the regulatory effects of 66 de-ubiquitinases on MCL1 in human embryonic kidney cells, and found that DUB3 was able to significantly raise MCL1 protein levels and was the most important de-ubiquitin enzyme to stabilize MCL1. DuB3 and MCL1 expression levels were also significantly associated in nine ovarian cancer cell line.
To verify the results, they conducted in-body and animal-level experiments, and the results showed that knocking down DUB3 by RNA interference technology could lead to apoptosis and slow proliferation of ovarian cancer cells, which could be reversed by the recovery experiment of MCL1. Stabilizing the expression of DUB3 can significantly promote the survival of ovarian cancer cells and drug resistance.
to figure out the molecular mechanism, the researchers wanted to find a suitable inhibitor to solve the clinical problem. After testing the regulatory effects of more than 30 inhibitors that have been clinically proven to be effective on DUB3, they found that Patrin-2 inhibited the high expression of DUB3. Patrin-2 has been shown to be an inhibitor of methyl transferase MGMT. Is MGMT possible to be associated with DUB3?
researchers found that over-expression of MGMT significantly increased the mRNA level of DUB3, and after 9 ovarian cancer cell line tests, also found a significant positive correlation between MGMT protein levels and DUB3 mRNA levels, indicating that MGMT transcription activates DUB3.
this point, the regulatory axis is stringed together. Patrin-2 has inhibitory effect on MGMT, MGMT can be trescribed to activate DUB3, and DUB3 is positively related to MCL1, plays a stable role in MCL1, MCL1 is an important protein against apoptosis, affecting ovarian cancer resistance.。 Patrin-2 also has its limitations, it only plays a significant role in the HIGH expression of DUB3 cells, Wu Xiaoxuan explained the relationship between the two, said: "DUB3 is like a thief, no thief, the police Patrin-2 does not play a role." If thieves are rampant, the police will naturally have to fight with all their strength. During
experiment, they also made an unexpected discovery. Previous studies have shown that HDAC family inhibitors in the inhibitor library have a role in inducing tumor apoptosis, but outside of this path, researchers have found that it also indirectly leads to an increase in the expression of the chemotherapy-resistant gene DUB3, which appears to be a "side effect."
if The use of Patrin-2 and HDAC inhibitors is equivalent to taking advantage of this 'side effect' of HDAC inhibitors, resulting in an increase in the number of 'thieves', which will increase the motivation of 'police' Patrin-2,"
said. This enables Patrin-2 to inhibit the anti-apoptosis protein MCL1 when DUB3 is low expression due to individual differences in ovarian cancer patients. Wu xiaoxuan said.
" our study reveals the important role of MGMT/DUB3/MCL1 regulatory axes in ovarian cancer resistance, and suggests that the combined use of Patrin-2 and HDAC inhibitors can effectively overcome ovarian cancer resistance, with potential applications in future clinical treatments. Liu Zhihua said.
, a researcher at the Kunming Institute of Zoology of the Chinese Academy of Sciences, said in an interview that ovarian cancer is a malignant gynaecological tumor that has not improved in five years. "This study has found that the known small-molecule drug intervention protein ubibin modification can overcome ovarian cancer resistance and has important theoretical and applied value." (Source: Liu Runan Li Chenyang, China Science Journal)
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