Journal Article

DKFZ-2024-01867

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png PDCD10 Is a Key Player in TMZ-Resistance and Tumor Cell Regrowth: Insights into Its Underlying Mechanism in Glioblastoma Cells.

Zhu, Y. ; Kim, S. N. ; Chen, Z.-R. ; Will, R.DKFZ* ; Zhong, R.-D. ; Dammann, P. ; Sure, U.

2024
MDPI Basel

Abstract: Overcoming temozolomide (TMZ)-resistance is a major challenge in glioblastoma therapy. Therefore, identifying the key molecular player in chemo-resistance becomes urgent. We previously reported the downregulation of PDCD10 in primary glioblastoma patients and its tumor suppressor-like function in glioblastoma cells. Here, we demonstrate that the loss of PDCD10 causes a significant TMZ-resistance during treatment and promotes a rapid regrowth of tumor cells after treatment. PDCD10 knockdown upregulated MGMT, a key enzyme mediating chemo-resistance in glioblastoma, accompanied by increased expression of DNA mismatch repair genes, and enabled tumor cells to evade TMZ-induced cell-cycle arrest. These findings were confirmed in independent models of PDCD10 overexpressing cells. Furthermore, PDCD10 downregulation led to the dedifferentiation of glioblastoma cells, as evidenced by increased clonogenic growth, the upregulation of glioblastoma stem cell (GSC) markers, and enhanced neurosphere formation capacity. GSCs derived from PDCD10 knockdown cells displayed stronger TMZ-resistance and regrowth potency, compared to their parental counterparts, indicating that PDCD10-induced stemness may independently contribute to tumor malignancy. These data provide evidence for a dual role of PDCD10 in tumor suppression by controlling both chemo-resistance and dedifferentiation, and highlight PDCD10 as a potential prognostic marker and target for combination therapy with TMZ in glioblastoma.

Keyword(s): Humans (MeSH) ; Glioblastoma: pathology (MeSH) ; Glioblastoma: genetics (MeSH) ; Glioblastoma: metabolism (MeSH) ; Glioblastoma: drug therapy (MeSH) ; Temozolomide: pharmacology (MeSH) ; Drug Resistance, Neoplasm: genetics (MeSH) ; Drug Resistance, Neoplasm: drug effects (MeSH) ; Cell Line, Tumor (MeSH) ; Apoptosis Regulatory Proteins: metabolism (MeSH) ; Apoptosis Regulatory Proteins: genetics (MeSH) ; Gene Expression Regulation, Neoplastic: drug effects (MeSH) ; Neoplastic Stem Cells: metabolism (MeSH) ; Neoplastic Stem Cells: pathology (MeSH) ; Neoplastic Stem Cells: drug effects (MeSH) ; Brain Neoplasms: pathology (MeSH) ; Brain Neoplasms: genetics (MeSH) ; Brain Neoplasms: metabolism (MeSH) ; Brain Neoplasms: drug therapy (MeSH) ; Membrane Proteins: metabolism (MeSH) ; Membrane Proteins: genetics (MeSH) ; Proto-Oncogene Proteins: metabolism (MeSH) ; Proto-Oncogene Proteins: genetics (MeSH) ; Cell Proliferation: drug effects (MeSH) ; DNA Modification Methylases: metabolism (MeSH) ; DNA Modification Methylases: genetics (MeSH) ; Tumor Suppressor Proteins: metabolism (MeSH) ; Tumor Suppressor Proteins: genetics (MeSH) ; DNA Repair Enzymes: metabolism (MeSH) ; DNA Repair Enzymes: genetics (MeSH) ; MGMT and MMR genes ; acquired TMZ-resistance ; glioblastoma (GBM) ; programmed cell death 10 (PDCD10) ; stemness ; Temozolomide ; Apoptosis Regulatory Proteins ; PDCD10 protein, human ; Membrane Proteins ; Proto-Oncogene Proteins ; DNA Modification Methylases ; MGMT protein, human ; Tumor Suppressor Proteins ; DNA Repair Enzymes

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Contributing Institute(s):

1. Zelluläre Tools (W111)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2024

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Database coverage:
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