Exosome-mediated RNAi of PAK4 prolongs survival of pancreatic cancer mouse model after loco-regional treatment

Xu, Lizhou; Faruqu, Farid N.; Lim, Yau Mun; Lim, Kee Y.; Liam‐Or, Revadee; Walters, Adam A.; Lavender, Paul; Fear, David; Wells, Claire M.; Wang, Julie; Al‐Jamal, Khuloud T.

doi:10.1016/j.biomaterials.2020.120369

Cited by 56 publications

(48 citation statements)

References 42 publications

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“…PC is currently one of the most lethal malignancies, with a low 5-year survival rate ( 26 ). Therefore, it is important to study the causative factors of its rapid proliferation and aggressive metastasis for early diagnosis and good prognosis of PC and for the development of effective therapeutic agents.…”

Section: Discussionmentioning

confidence: 99%

HOXD9‑induced SCNN1A upregulation promotes pancreatic cancer cell proliferation, migration and predicts prognosis by regulating epithelial‑mesenchymal transformation

Chang

Nan³

et al. 2021

Mol Med Rep

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Pancreatic cancer (PC) is a malignant tumor disease, whose molecular mechanism is not fully understood. Sodium channel epithelial 1α subunit (SCNN1A) serves an important role in tumor progression. The current study explored the role of homeobox D9 (HOXD9) and SCNN1A in the progression of PC. The expression of SCNN1A and HOXD9 in PC samples was predicted on online databases and detected in PC cell lines. The association between SCNN1A expression and PC prognosis was examined by the Gene Expression Profiling Interactive Analysis, The Cancer Genome Atlas and Genotype-Tissue Expression databases and by a Kaplan-Meier plotter. Subsequently, the biological effects of SCNN1A on PC cell growth, colony formation, migration and invasion were investigated through RNA interference and cell transfection. Next, the expression of E-cadherin, N-cadherin, Vimentin and Snail was detected by western blotting to discover whether HOXD9 dysregulation mediated PC metastasis. Binding sites of HOXD9 and SCNN1A promoters were predicted on JASPAR. Reverse transcription-quantitative PCR and western blotting were used to detect the expression level of SCNN1A following interference and overexpression of HOXD9. Luciferase assay detected luciferase activity following interference with HOXD9 and the transcriptional activity of SCNN1A following binding site deletion. High expression of SCNN1A and HOXD9 in PC was predicted by online databases, signifying poor prognosis. The present study confirmed the above predictions in PC cell lines. Knockdown of SCNN1A and HOXD9 could effectively inhibit the proliferation, migration, invasion and epithelial-mesenchymal transition of PC cells. Furthermore, HOXD9 activated SCNN1A transcription, forming a feedback regulatory loop. HOXD9 was demonstrated to activate SCNN1A and promote the malignant biological process of PC.

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Section: Discussionmentioning

confidence: 99%

HOXD9‑induced SCNN1A upregulation promotes pancreatic cancer cell proliferation, migration and predicts prognosis by regulating epithelial‑mesenchymal transformation

Chang

Nan³

et al. 2021

Mol Med Rep

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“…PAK4-a member of the PAK family of serine threonine kinases, linked with PI3K/AKT and Wnt/β-catenin signaling-has been identified as a promising therapeutic target in cancer [211,212]. With two small molecule inhibitors of PAK4 currently being evaluated in Phase I basket trials in solid malignancies and non-Hodgkin lymphoma (NCT04281420, NCT02702492), Xu et al recently reported that PAK4 could also be targeted by sEV-siRNA [208]. Authors loaded PDAC-derived sEVs with PAK4-targeted siRNA (siPAK4) by electroporation.…”

Section: Sevs As Delivery Vehicles For Ncrna-based Therapy In Pdacmentioning

confidence: 99%

“…Authors loaded PDAC-derived sEVs with PAK4-targeted siRNA (siPAK4) by electroporation. Subsequent intratumoral injection of siPAK4 sEVs into murine PANC-1 xenografts proved to be highly efficient in slowing down tumor growth and prolonging overall survival of mice, while at the same time exhibiting a tolerable safety profile in regard to liver toxicity [208]. It should be noted, however, that although tumor sEVs have been shown to distribute preferentially to tumor tissue, the utilization of tumor sEVs as delivery vehicles seems questionable in a clinical setting [213].…”

Section: Sevs As Delivery Vehicles For Ncrna-based Therapy In Pdacmentioning

confidence: 99%

Small extracellular vesicle non-coding RNAs in pancreatic cancer: molecular mechanisms and clinical implications

Reese

Dhayat

2021

J Hematol Oncol

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Pancreatic cancer has the worst prognosis among common tumors which is attributed to its aggressive phenotype, diagnosis at advanced, inoperable stages, and resistance to systemic therapy. Non-coding RNAs (ncRNAs) such as microRNAs, long non-coding RNAs, and circular RNAs have been established as important regulators of gene expression and their deregulation has been implicated in multiple diseases and foremost cancer. In the tumor microenvironment, non-coding RNAs can be distributed among cancer cells, stromal cells, and immune cells via small extracellular vesicles (sEVs), thereby facilitating intercellular communication and influencing major cancer hallmarks such as angiogenesis, evasion of the immune system, and metastatic dissemination. Furthermore, sEV-ncRNAs have shown promising potential as liquid biopsies with diagnostic and prognostic significance. In this review, we summarize the role of sEVs as carriers of ncRNAs and underlying molecular mechanisms in pancreatic cancer. Moreover, we review the potential of sEV-ncRNAs as biomarkers and highlight the suitability of sEVs as delivery vehicles for ncRNA-based cancer therapy.

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“…To further increase the efficacy of drugs, including those targeting PAKs, novel nanoparticles are currently being tested [ 38 , 57 , 58 ]. In recent years, nanoparticles (NPs) have attracted increasing attention as drug carriers, due to their excellent ability to stably encapsulate drugs, facilitate drug delivery, and prolong circulation time.…”

Section: Introductionmentioning

confidence: 99%

“…NPs have attracted attention as drug carriers, due to their excellent ability to stably encapsulate drugs, facilitate drug delivery, and prolong circulation time [ 86 ]. As discussed throughout this proposal, several studies have shown more promising results when PAK inhibitors are combined with the use of nanomedicine, compared with free PAK inhibitors [ 38 , 57 , 84 , 86 ]. The use of nanoparticles can stabilize the pharmacokinetics of poorly water-soluble drugs, resulting in improved pharmacological activity, enhanced biodistribution, and even the ability to pass barriers such as the blood–brain barrier (BBB) [ 87 , 88 ].…”

Section: Introductionmentioning

confidence: 99%

The Use of Nanomedicine to Target Signaling by the PAK Kinases for Disease Treatment

Wang¹,

Minden²

2021

Cells

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P21-activated kinases (PAKs) are serine/threonine kinases involved in the regulation of cell survival, proliferation, inhibition of apoptosis, and the regulation of cell morphology. Some members of the PAK family are highly expressed in several types of cancer, and they have also been implicated in several other medical disorders. They are thus considered to be good targets for treatment of cancer and other diseases. Although there are several inhibitors of the PAKs, the utility of some of these inhibitors is reduced for several reasons, including limited metabolic stability. One way to overcome this problem is the use of nanoparticles, which have the potential to increase drug delivery. The overall goals of this review are to describe the roles for PAK kinases in cell signaling and disease, and to describe how the use of nanomedicine is a promising new method for administering PAK inhibitors for the purpose of disease treatment and research. We discuss some of the basic mechanisms behind nanomedicine technology, and we then describe how these techniques are being used to package and deliver PAK inhibitors.

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Exosome-mediated RNAi of PAK4 prolongs survival of pancreatic cancer mouse model after loco-regional treatment

Cited by 56 publications

References 42 publications

HOXD9‑induced SCNN1A upregulation promotes pancreatic cancer cell proliferation, migration and predicts prognosis by regulating epithelial‑mesenchymal transformation

HOXD9‑induced SCNN1A upregulation promotes pancreatic cancer cell proliferation, migration and predicts prognosis by regulating epithelial‑mesenchymal transformation

Small extracellular vesicle non-coding RNAs in pancreatic cancer: molecular mechanisms and clinical implications

The Use of Nanomedicine to Target Signaling by the PAK Kinases for Disease Treatment

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