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ShRNA-based POLD2 expression knockdown sensitizes glioblastoma to DNA-Damaging therapeutics
Qingfu Xu1, Chengchen Hu2, Yan Zhu3
1Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, 510623, PR China; Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, PR China; Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21287, USA.
Abstract:
Glioblastoma (GBM) has limited therapeutic options. DNA repair mechanisms contribute GBM cells to escape therapies and re-establish tumor growth. Multiple studies have shown that POLD2 plays a critical role in DNA replication, DNA repair and genomic stability. We demonstrate for the first time that POLD2 is highly expressed in human glioma specimens and that expression correlates with poor patient survival. siRNA or shRNA POLD2 inhibited GBM cell proliferation, cell cycle progression, invasiveness, sensitized GBM cells to chemo/radiation-induced cell death and reversed the cytoprotective effects of EGFR signaling. Conversely, forced POLD2 expression was found to induce GBM cell proliferation, colony formation, invasiveness and chemo/radiation resistance. POLD2 expression associated with stem-like cell subsets (CD133+ and SSEA-1+ cells) and positively correlated with Sox2 expression in clinical specimens. Its expression was induced by Sox2 and inhibited by the forced differentiation of GBM neurospheres. shRNA-POLD2 modestly inhibited GBM neurosphere-derived orthotopic xenografts growth, when combined with radiation, dramatically inhibited xenograft growth in a cooperative fashion. These novel findings identify POLD2 as a new potential therapeutic target for enhancing GBM response to current standard of care therapeutics.
Insights
Pol2 (DNA polymerase delta 2) is highly expressed in glioblastoma, promoting tumor growth and resistance to therapy. Inhibiting Pol2 can enhance glioblastoma treatment effectiveness when combined with standard therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Glioblastoma (GBM) presents limited therapeutic options, with DNA repair mechanisms enabling tumor cell survival.
- Pol2 (DNA polymerase delta 2) is crucial for DNA replication, repair, and genomic stability.
Purpose of the Study:
- To investigate the role of POLD2 in glioblastoma development and its potential as a therapeutic target.
- To determine the correlation between POLD2 expression and patient survival and its association with stem-like cell markers.
Main Methods:
- Analysis of POLD2 expression in human glioma specimens.
- Inhibition of POLD2 using siRNA/shRNA in GBM cell lines and neurospheres.
- Assessment of GBM cell proliferation, cell cycle, invasiveness, and response to chemo/radiation therapy.
- Evaluation of POLD2 expression in relation to stem-like cell markers (CD133, SSEA-1) and Sox2.
- In vivo studies using orthotopic xenografts in combination with radiation therapy.
Main Results:
- POLD2 is highly expressed in human glioma, correlating with poor patient survival.
- POLD2 inhibition reduced GBM cell proliferation, invasiveness, and sensitized cells to chemo/radiation.
- POLD2 expression is associated with stem-like cell populations and Sox2, and is regulated by Sox2.
- Combined POLD2 inhibition and radiation significantly reduced tumor growth in vivo.
Conclusions:
- POLD2 plays a significant role in glioblastoma progression and therapeutic resistance.
- POLD2 represents a novel therapeutic target for improving glioblastoma treatment outcomes.
- Targeting POLD2 in combination with standard therapies may enhance treatment efficacy for glioblastoma patients.
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