Mechanism Of Bromophenol Compounds On Insulin Resistance Amelioration And Anti-pancreatic Cancer By Targeting PTP1B

Protein tyrosine phosphatase 1 B（PTP1B）has emerged as a well-established regulator in numerous metabolic processes,and is closely related with the occurrence and development of diseases.Especially in type 2 diabetes and tumors,PTP1B plays an important role,so inhibitors targeting PTP1B are widely concerned.In order to meet the increasing demand for diabetes treatment,many pharmaceutical companies are committed to the development of PTP1B inhibitors.However,the development of PTP1B inhibitors encounters many obstacles,such as poor membrane permeability,so it is very important to develop new PTP1B inhibitors with novel structure,excellent inhibitory activity and good membrane permeability.In the previous study,BPN was isolated from the red alga Rhodomela confervoides and displayed the significant PTP1B inhibitory activity with an IC₅₀ of 0.84μM.Further studies have shown that BPN penetrated into C2C12 myotubes and inhibited PTP1B activity via binding strongly to the catalytic site through forming hydrogen bonds with Lys120,Asp48 and Asp180,which not only activated insulin signaling pathway at the basal level,but also improved palmitate-induced insulin resistance through augmenting insulin sensitivity,and ultimately increased glucose uptake through glucose transporter4（GLUT4）translocation.It has been found that PTP1B also plays an important role in oncogenesis.Inhibition of PTP1B leads to inhibition of tumor growth and metastasis.The PTP1B inhibitor——MSI-1436C,a potential drug for diabetes,is now being tested in a phase I clinical trial for the treatment of metastatic breast cancer.Therefore,PTP1B inhibitors also have great potential in the treatment of cancer.Pancreatic cancer is a highly malignant gastrointestinal tumor.There is no effective treatment.The reliability of molecular targeted therapy urges us to discover new therapeutic targets for pancreatic cancer.Because PTP1B is the target of diabetes mellitus and obesity,which are two established risk factors for PDAC,it is important to determine the roles of PTP1B in pancreatic cancer.However,the role of PTP1B in pancreatic cancer remains elusive.In previous study,a series of bromophenol compounds were synthesized based on BPN,among which,LXQ46 showed the most significant PTP1B inhibitory activity.Hence,in this study,we used LXQ46 as a small molecule probe to study the feasibility of PTP1B as a therapeutic target for pancreatic cancer.The results showed that PTP1B was highly expressed in pancreatic cancer tissues and positively correlated with distant metastasis and tumor stage of pancreatic cancer,and negatively correlated with postoperative survival time.Loss of PTP1B led to slower growth,cycle arrest and migration inhibition of pancreatic cancer cells.In vivo study showed that PTP1B knockdown inhibited tumor formation and growth.Conversely,PTP1B overexpression promoted pancreatic cancer cell proliferation and migration.These results indicated that PTP1B acts as an oncogene in pancreatic cancer,and the inhibition of PTP1B could inhibit cancer progression.Therefore,we used PTP1B specific inhibitor LXQ46 for further research and found that LXQ46 significantly inhibited the PDAC cell proliferation,migration and tumor growth.These results further demonstrated that pharmacological inhibition of PTP1B showed potent therapeutic efficacy on pancreatic cancer in vivo,which supported the notion of PTP1B as a promising therapeutic target for PDAC.Mechanism studies revealed that PTP1B targeted the PKM2/AMPK/mTOC1 signaling pathway to regulate PDAC cell growth.PTP1B inhibition increased PKM2 Tyr-105 phosphorylation to further result in significant activation of AMPK,which decreased mTOC1 activity and led to inhibition of p70S6K.Meanwhile,the decreased phosphorylation of PRAS40 regulated by PKM2also helped to inhibit mTOC1.Collectively,these results strongly suggest the potential of PTP1B as a therapeutic target in PDAC and the study value of a PTP1B inhibitor in the treatment of pancreatic cancer.Collectively,in this study,we used bromophenol compounds to inhibit PTP1B activity to study the mechanism of PTP1B inhibitors in diabetes and pancreatic cancer.One the one hand,the results revealed that BPN represents a potential candidate for further development as an antidiabetic agent targeting PTP1B and can be used as a lead compound for the design of other novel therapeutic drugs for type 2 diabetes.On the other hand,the results demonstrated that PTP1B is a potential biomarker for early PDAC diagnosis and suggested the potential of PTP1B as a therapeutic target in PDAC and the study value of PTP1B inhibitors in the treatment of pancreatic cancer.In summary,this study identified the great therapeutic potential by targeting PTP1B in the treatment of diabetes and cancer,and provided the research basis for the application of PTP1B inhibitors in the treatment of these two metabolic diseases.