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Published on: December 19, 2019
TP53 Genotype-Dependent Cellular Responses to DVDMS-Sonodynamic Therapy in Oral Squamous Cell Carcinoma
Guo-Gang Dong1, Pin-Xiu Pan2, Feng-Ting Zhang2
1Department of Anatomy, School of Basic Medical Sciences, Harbin Medical University, Harbin, China; Department of Radiology, Jinling Hospital Affiliated to the Medical School of Nanjing University, Nanjing, China.
Objective:
This study aimed to assess the inhibitory effects and underlying mechanisms of sonodynamic therapy (SDT) mediated by the novel sonosensitizer sinoporphyrin sodium (DVDMS) in oral squamous cell carcinoma (OSCC) cells exhibiting distinct TP53 genotypes.
Methods:
Cytotoxicity, intracellular uptake and localization of DVDMS, reactive oxygen species (ROS) levels, apoptosis and autophagy were assessed in two OSCC cell lines (SAS and HSC-3). Expression levels of p53, Bax, Bcl-2 and LC3B proteins were analyzed. The p53 inhibitor pifithrin-α (PFT-α) was utilized to determine its modulatory effects on SDT-induced cellular responses in SAS cells.
Results:
DVDMS-mediated SDT significantly inhibited cell proliferation in both SAS and HSC-3 lines. DVDMS predominantly accumulated in the mitochondria, with higher colocalization observed in SAS cells. SDT induced a marked elevation in intracellular ROS and mitochondrial apoptosis, particularly in SAS cells. After 2 h of SDT, there was a significant decrease in autophagic activity in SAS cells, whereas an increase was noted in HSC-3 cells. In SAS cells, SDT resulted in significant upregulation and nucleocytoplasmic translocation of p53 protein. Treatment with PFT-α partially attenuated apoptosis, reversed autophagy inhibition and suppressed p53 translocation in SAS cells.
Conclusion:
DVDMS-mediated SDT elicited greater cytotoxic responses in OSCC cells harboring wild-type TP53 (SAS) compared to mutant TP53 (HSC-3) cells. The therapy induced mitochondrial apoptosis and modulated autophagy in both cell lines, with more pronounced responses observed in wild-type TP53 cells. These findings suggest that p53 plays a critical regulatory role in mediating SDT-induced mitochondrial apoptosis and autophagy under DVDMS sensitization in OSCC.
Insights
Sonodynamic therapy (SDT) with sinoporphyrin sodium (DVDMS) effectively inhibited oral squamous cell carcinoma (OSCC) growth, with greater impact on wild-type TP53 cells. The therapy induced apoptosis and modulated autophagy, highlighting p53
Area of Science:
- Biomedical Engineering
- Oncology
- Molecular Biology
Background:
- Oral squamous cell carcinoma (OSCC) presents challenges in treatment, necessitating novel therapeutic strategies.
- Sonodynamic therapy (SDT) offers a non-invasive approach for cancer treatment.
- The role of TP53 genotype in therapeutic response remains an area of active investigation.
Purpose of the Study:
- To evaluate the efficacy of SDT using sinoporphyrin sodium (DVDMS) in OSCC cells.
- To elucidate the underlying mechanisms of DVDMS-mediated SDT, focusing on TP53 genotype variations.
- To assess the impact of SDT on cell proliferation, apoptosis, autophagy, and reactive oxygen species (ROS) generation.
Main Methods:
- Two OSCC cell lines (SAS and HSC-3) with distinct TP53 genotypes were used.
- Cytotoxicity, DVDMS uptake, ROS levels, apoptosis, and autophagy were measured.
- Protein expression (p53, Bax, Bcl-2, LC3B) and p53 inhibition were analyzed.
Main Results:
- DVDMS-mediated SDT significantly inhibited proliferation in both cell lines.
- SDT induced higher ROS levels and mitochondrial apoptosis in wild-type TP53 (SAS) cells compared to mutant TP53 (HSC-3) cells.
- DVDMS-mediated SDT modulated autophagy differently between cell lines and involved p53 translocation in SAS cells.
Conclusions:
- DVDMS-mediated SDT demonstrates greater efficacy in OSCC cells with wild-type TP53.
- The therapy induces mitochondrial apoptosis and modulates autophagy, with p53 playing a key regulatory role.
- These findings support the potential of DVDMS-based SDT for OSCC treatment, particularly in patients with wild-type TP53.
