The massive infiltration of suppressor immune cells within the tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is a major cause of treatment resistance. Reducing this infiltration may represent a potentially effective therapeutic strategy. Sphingomyelin synthase 2 (SMS2) is a crucial enzyme for sphingomyelin synthesis, contributing significantly to the integrity and function of the plasma membrane. In this study, we developed a self-assembling SMS2 siRNA gene expression plasmid for in vivo delivery. The SMS2 siRNA specifically inhibits SMS2 expression while preserving the expression and activity of SMS1. Administration of the self-assembling SMS2 siRNA suppresses tumor growth in a murine model of Panc02 pancreatic carcinoma, modulates the polarization of tumor-associated macrophages (TAMs), and reduces the infiltration of tumor-associated neutrophils (TANs) by regulating the NF-κB/CXCL5 pathway. Consequently, utilizing SMS2 siRNA to improve the local immunosuppressive microenvironment holds promise for pancreatic cancer therapy.
Shu Dong,MD,Panling Xu,MD,Peiwen Yang,MD,Juying Jiao,MD,Chien-shan Cheng,MD,PhD,Lianyu Chen,MD,PhD
BackgroundHuanglianjiedu decoction (HLJDD) is a classical Traditional Chinese Medicine (TCM) prescription with thousand years of clinical use against various malignancies, including pancreatic adenocarcinoma (PAAD). However, its potential bioactive component and molecular mechanism remains unclear.AimsThis study is to inspect the HLJDD mechanisms of action against PAAD via integrated computational and pharmacochemistry strategy, in vivo and in vitro experiments to validate associated targets and pathways.MethodsA PAAD xenograft model was established by subcutaneous injecting Panc02 cells into C57BL/6 mice. Ultra-high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) was engaged to determine constituents of HLJDD and assessed for pharmacokinetic scheme using the TCM Systems Pharmacology Platform (TCM-SP). Differentially expressed genes (DEGs) of PAAD was retrieved from the transcriptome dataset GSE43795, followed by recognizing overlapping targets the oncogenes and target genes of PAAD and HLJDD, respectively. Putative signaling pathways of HLJDD in treating PAAD were enriched using KEGG and GO analyses. The anti-PAAD effects of HLJDD was assessed in vivo and in vitro, besides, the potential mechanism was validated using immunoblotting and immunohistochemical assays.ResultsHLJDD significantly suppressed the growth of transplanted PAAD tumors, constrained PAAD progression, and induced apoptosis and S-phase arrest. Seventy-five active components meeting the drug-likeness criteria and 278 target genes of HLJDD were identified. KEGG analysis indicated that the top three enriched pathways were cancer, AGE-RAGE signaling, and IL-17 signaling pathways. Disease enrichment analysis highlighted immune, pharmacological, and cancer-related diseases as the top three categories. A total of 47 potential target genes were identified. Immunoblotting revealed that HLJDD inhibited PI3K and MAPK-related signaling pathways, while immunohistochemical staining confirmed that HLJDD suppressed the expression of phosphorylated MAPK and ERK1/2.ConclusionHLJDD inhibited PAAD in vitro and in vivo via the modulation of multiple mechanisms, including regulation of PI3K/AKT/mTOR and MAPK/ERK1/2 signaling pathways.
Zhenjiang Zheng,Dingchuan Peng,Mengfei Li,Xuehan Lu,Songlin Gong,Yuan Yuan,Epiphane K. Silli,Jiali Tang,Qiaoyun Zhao,HaoYun Xu,Yufei Lan,Chunlu Tan,Ying Wang
Due to the malignant proliferation and severe tumor fibrosis of pancreatic cancer (PC), the efficacy of chemotherapy has been largely limited. Peptidyl-prolyl cis -trans isomerase NIMA-interacting 1 (Pin1) promotes tumor progression by promoting collagen synthesis and tumor cell proliferation . In this study, we developed nano-liposomes (FU-GEM/Pin1 siRNA@LIP) that act simultaneously on pancreatic tumor cells. FU-GEM/Pin1 siRNA@LIP were designed with suitable particle size and potential, and effectively loaded with Pin1 siRNA and fucoidan (FU) while demonstrating good release stability and biocompatibility . Our study showed that FU-GEM/Pin1 siRNA@LIP effectively inhibited the proliferation of Panc01 and Panc02 tumor cells and significantly enhanced the uptake of these two types of cells in vitro . FU-GEM/Pin1 siRNA@LIP might cause tumor damage, promote apoptosis and reduce collagen formation in vivo . Molecular and histological studies demonstrated that FU-GEM/Pin1 siRNA@LIP regulated the expression of CDH11 and α-SMA, and also reducing collagen synthesis of peripheral matrix. In summary, our experiments highlight that FU-GEM/Pin1 siRNA@LIP is an effective combination delivery system. It can inhibit tumor cell proliferation in vitro , promote tumor cell apoptosis and reduce collagen synthesis in vivo . This system could provide a promising therapeutic option for PC.
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