The Key Role Of LXR?-SREBF1-PNKP Axis In Pancreatic Cancer DNA Repair And Its Intervention

Pancreatic cancer is one of the most intractable malignant tumors,which is known as the king of cancer.The five-year survival rate of pancreatic cancer patients is only 6%,and the incidence of the cancer is increasing every year in the world.Pancreatic cancer has become one of the malignant tumors that seriously threaten human life and health.The 5-year survival rate of patients with stage ? and stage ? pancreatic cancer is less than 20%after surgery and drug treatment.For a long time,the survival time of the patients with advanced pancreatic cancer(stage ? and ?)is only 3-9 months due to the lack of effective treatment methods and drugs.The pathogenesis of pancreatic cancer is still unknown,and the lack of effective anti-pancreatic cancer drugs has become an urgent scientific problem to be solved.Recent studies show that DNA repair is defective in pancreatic cancer.The number of DNA strand breaks is approximate 8 times higher than that in nonnal tissues.An increase in the number of DNA strand breaks causes chromosome translocation and enhanced gene mutation,which produces a variety of fusion genes and oncogenes,and drives tumorigenesis and malignant tumor development.However,many classical DNA repair genes and pathways in malignant tumor cells are highly activated,such as ATM,ATR,DNA-PK and PARP.The mechanism underlying DNA repair defects in cancer cells is still enigmatic.We speculate that there are some key DNA repair genes or signaling pathways in pancreatic cancer that have not yet been discovered.Through bioinformatics analysis and screening of anti-pancreatic cancer drugs from the traditional Chinese medicinal herbs,we found that the candidate gene PNKP may be responsible for DNA repair defect in pancreatic cancer,and carried out a series of studies to explore the possibility using the sample from clinical pancreatic cancer patients,mouse transplanted tumor model,cell biology,molecular biology and protein chemistry.Our study reveals that:(1)PNKP is abnormally low expression in the tumor tissues from the pancreatic cancer patients,and its expression level is negatively correlated with the stage of pancreatic cancer.That is,the lower the expression of PNKP,the higher the stage of the pancreatic cancer,and the higher malignancy.The expression level of PNKP is closely related to the ability of DNA repair in pancreatic cancer cells,and its abnormal low expression is one of the key reasons for DNA repair defects.(2)PNKP gene transcription is regulated by its upstream transcription factors LXRa and SREBF1.We found that LXRa-SREBF1-PNKP is a new signal pathway to control DNA repair pathway and plays a pivotal role in the repair of DNA damage in pancreatic cancer.The low activity of the LXRa-SREBF1-PNKP pathway is one of the important reasons for DNA repair defects in pancreatic cancer cells.(3)Triptonide(TN)has a strong anti-pancreatic cancer effect.We demonstrated that LXRa is an intracellular TN receptor.TN binds to LXRa and has an extreme high affinity(Kd=0.14 nM).TN inactivates LXRa,inhibits the LXRa-SREBF1-PNKP pathway,and increases DNA strand breaks in pancreatic cancer cells,consequently activating the intracellular MEK4-MK4-p38 pathway;then,the tumor suppressor gene p53 is highly activated,which promotes the overexpression of the tumor suppressor gene p21 and reduces the level of CDK3,eventually leads to mitotic catastrophe and apoptosis of pancreatic cancer cells.We found a new LXRa-SREBF1-PNKP pathway that control DNA repair in pancreatic cancer cells,providing a new strategy and approach for the study of cancer pathogenesis and anti-cancer.Catching the vulanerable spot of cancer cells,we further inhibited the function-defective LXRa-SREBF1-PNKP pathway in pancreatic cancer,which aggravated DNA damage and led to cancer cell apoptosis.The LXRa-SREBF1-PNKP pathway in normal tissue cells has high activity of the LXRa-SREBF1-PNKP pathway and low level of DNA strand breaks,thus,TN has no obvious toxicity to normal cells within the effective doses of anti-cancer and exerts a selective anti-cancer effect.Collectively,our study provides new ideas for anti-cancer research,and also offers potential targets and new approaches for the development of anti-pancreatic cancer drugs,particularly we find effective anti-cancer monomer components from the traditional Chinese medicine,therefore providing new strategies for the treatment of pancreatic cancer.