Nanoparticle-Mediated Therapy with miR-198 Sensitizes Pancreatic Cancer to Gemcitabine Treatment through Downregulation of VCP-Mediated Autophagy.
Christian Marin-MullerDali LiJian-Ming LüZhengdong LiangOsvaldo Vega-MartínezSue E CrawfordMary K EstesWilliam E FisherChangyi ChenQizhi Cathy YaoPublished in: Pharmaceutics (2023)
Pancreatic ductal adenocarcinoma (PDAC) remains an extremely aggressive disease characterized by rapidly acquired multi-drug resistance, including to first-line chemotherapeutic agent gemcitabine. Autophagy is a process that is often exploited by cancer and is one of several intrinsic factors associated with resistance to gemcitabine. We have previously found that miR-198 acts as a tumor suppressor in PDAC through the targeting of factors including Valosin-containing protein (VCP). VCP has been reported to play an important role in autophagic flux. In this study, we investigated whether the repression of VCP through miR-198 administration disrupts the autophagy process and sensitizes PDAC cells to gemcitabine treatment in vitro. Moreover, we used LGA-PEI (LPNP) nanoparticles to effectively administer miR-198 to tumors in vivo, inducing tumor sensitization to gemcitabine and leading to a significant reduction in tumor burden and metastases and a concomitant downregulation of VCP expression and autophagy maturation. Our results indicate a potential therapeutic strategy for targeting gemcitabine resistant PDAC and establishes the use of LPNPs for effective therapeutic delivery of nucleic acids in vitro and in vivo.
Keyphrases
- cell proliferation
- induced apoptosis
- cell death
- endoplasmic reticulum stress
- long non coding rna
- signaling pathway
- locally advanced
- long noncoding rna
- oxidative stress
- poor prognosis
- cell cycle arrest
- rectal cancer
- pi k akt
- squamous cell carcinoma
- stem cells
- mass spectrometry
- risk factors
- small molecule
- amino acid
- cell therapy
- mesenchymal stem cells