Honokiol Suppresses Perineural Invasion of Pancreatic Cancer by Inhibiting SMAD2/3 Signaling

Abstract

BackgroundPerineural invasion (PNI) is an important pathologic feature of pancreatic cancer, and the incidence of PNI in pancreatic cancer is 70%-100%. PNI is associated with poor outcome, metastasis, and recurrence in pancreatic cancer patients. There are very few treatments for PNI in pancreatic cancer. Honokiol (HNK) is a natural product that is mainly obtained from Magnolia species and has been indicated to have anticancer activity. HNK also has potent neurotrophic activity and may be effective for suppressing PNI. However, the potential role of HNK in the treatment of PNI in pancreatic cancer has not been elucidated.MethodsIn our study, pancreatic cancer cells were treated with vehicle or HNK, and the invasion and migration capacities were assessed by wound scratch assays and Transwell assays. A cancer cell-dorsal root ganglion coculture model was established to evaluate the effect of HNK on the PNI of pancreatic cancer. Western blotting was used to detect markers of EMT and neurotrophic factors in pancreatic tissue. Recombinant TGF-β1 was used to activate SMAD2/3 to verify the effect of HNK on SMAD2/3 and neurotrophic factors. The subcutaneous tumor model and the sciatic nerve invasion model, which were established in transgenic engineered mice harboring spontaneous pancreatic cancer, were used to investigate the mechanism by which HNK inhibits EMT and PNI in vivo.ResultsWe found that HNK can inhibit the invasion and migration of pancreatic cancer cells. More importantly, HNK can inhibit the PNI of pancreatic cancer. The HNK-mediated suppression of pancreatic cancer PNI was partially mediated by inhibition of SMAD2/3 phosphorylation. In addition, the inhibitory effect of HNK on PNI can be reversed by activating SMAD2/3. In vivo, we found that HNK can suppress EMT in pancreatic cancer. HNK can also inhibit cancer cell migration along the nerve, reduce the damage to the sciatic nerve caused by tumor cells and protect the function of the sciatic nerve.ConclusionOur results demonstrate that HNK can inhibit the invasion, migration, and PNI of pancreatic cancer by blocking SMAD2/3 phosphorylation, and we conclude that HNK may be a new strategy for suppressing PNI in pancreatic cancer.

Nodal Enhances Perineural Invasion in Pancreatic Cancer by Promoting Tumor-Nerve Convergence

“…We further wanted to demonstrate whether Nodal accelerates PNI of pancreatic cancer cells. An in vitro peripheral neural invasion model was created using pancreatic cancer cells with DRGs in Matrigel according to previous reported models [ 19 , 20 ]. During the coculture period of pancreatic cancer cells (Panc-1 and BxPC-3) and DRGs, we found that the DRG synaptic boundary and pancreatic cancer cell boundary moved toward each other more obviously in the Nodal intervention group than in the control group.…”

Clinical Efficacy and Safety of Traditional Medicine Preparations Combined With Chemotherapy for Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis

“…At present, various TMPs containing diverse bioactive molecules have been shown to exhibit multiple anti-pancreatic cancer effects. These compounds, including quercetin ( 64 ), baicalein ( 65 ), honokiol ( 66 ), luteolin ( 67 ), and silibinin ( 68 ), have been found to be present in numerous TMPs. They can suppress pancreatic cancer cell proliferation or induce apoptotic and autophagic by modulating various oncogenic pathways including Wnt, phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin, mitogen-activated protein kinases and Nuclear factor-kappa B pathways ( 69 ).…”

Honokiol inhibits SARS-CoV-2 replication in cell culture

“…HK is also able to down-regulate NF-κB and STAT3 [18,20], both of which are generally involved in tumor promotion [28]. Other targets of HK include Sirt3 [19], Nrf2 [29], MAPK [30], and SMAD [31] signaling pathways. Some of these factors, such as Nrf2, Sirt3, mTOR [32][33][34] have been linked to pathways involved in antiviral responses.…”