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Protein Disulfide Isomerase A3 (PDIA3): A Pharmacological Target in Glioblastoma?
Giuliano Paglia1, Marco Minacori1, Giorgia Meschiari1
1Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P. le Aldo Moro 5, 00185 Rome, Italy.
Abstract:
The protein disulfide isomerase A3 (PDIA3) is directly or indirectly involved in various physiopathological processes and participates in cancer initiation, progression and chemosensitivity. However, little is known about its involvement in glioblastoma. To obtain specific information, we performed cellular experiments in the T98G and U-87 MG glioblastoma cell lines to evaluate the role of PDIA3. The loss of PDIA3 functions, either through inhibition or silencing, reduced glioblastoma cells spreading by triggering cytotoxic phenomena. PDIA3 inhibition led to a redistribution of PDIA3, resulting in the formation of protein aggregates visualized through immunofluorescence staining. Concurrently, cell cycle progression underwent arrest at the G1/S checkpoint. After PDIA3 inhibition, ROS-independent DNA damage and the activation of the repair system occurred, as evidenced by the phosphorylation of H2A.X and the overexpression of the Ku70 protein. We also demonstrated through a clonogenic assay that PDIA3 inhibition could increase the chemosensitivity of T98G and U-87 MG cells to the approved glioblastoma drug temozolomide (TMZ). Overall, PDIA3 inhibition induced cytotoxic effects in the analyzed glioblastoma cell lines. Although further in vivo studies are needed, the results suggested PDIA3 as a novel therapeutic target that could also be included in already approved therapies.
Insights
Inhibiting protein disulfide isomerase A3 (PDIA3) in glioblastoma cells triggers cell death and DNA damage. This inhibition also enhances sensitivity to temozolomide, suggesting PDIA3 as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Protein disulfide isomerase A3 (PDIA3) is implicated in various physiological and pathological processes, including cancer progression and chemosensitivity.
- Its specific role in glioblastoma, a highly aggressive brain tumor, remains largely unexplored.
Purpose of the Study:
- To investigate the function of PDIA3 in glioblastoma.
- To evaluate PDIA3 as a potential therapeutic target for glioblastoma treatment.
Main Methods:
- Cellular experiments were conducted using T98G and U-87 MG glioblastoma cell lines.
- PDIA3 function was inhibited or silenced to assess its effects.
- Immunofluorescence staining, cell cycle analysis, DNA damage assays, and clonogenic assays were employed.
Main Results:
- Loss of PDIA3 function reduced glioblastoma cell spreading via cytotoxic effects and G1/S cell cycle arrest.
- PDIA3 inhibition induced ROS-independent DNA damage and activated DNA repair mechanisms (H2A.X phosphorylation, Ku70 overexpression).
- PDIA3 inhibition increased glioblastoma cell sensitivity to temozolomide (TMZ).
Conclusions:
- PDIA3 inhibition exerts cytotoxic effects on glioblastoma cells.
- PDIA3 represents a potential therapeutic target for glioblastoma, possibly in combination with existing therapies like TMZ.
