TY  - JOUR
AU  - Zhu, Yuan
AU  - Kim, Su Na
AU  - Chen, Zhong-Rong
AU  - Will, Rainer
AU  - Zhong, Rong-De
AU  - Dammann, Philipp
AU  - Sure, Ulrich
TI  - PDCD10 Is a Key Player in TMZ-Resistance and Tumor Cell Regrowth: Insights into Its Underlying Mechanism in Glioblastoma Cells.
JO  - Cells
VL  - 13
IS  - 17
SN  - 2073-4409
CY  - Basel
PB  - MDPI
M1  - DKFZ-2024-01867
SP  - 1442
PY  - 2024
AB  - 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.
KW  - Humans
KW  - Glioblastoma: pathology
KW  - Glioblastoma: genetics
KW  - Glioblastoma: metabolism
KW  - Glioblastoma: drug therapy
KW  - Temozolomide: pharmacology
KW  - Drug Resistance, Neoplasm: genetics
KW  - Drug Resistance, Neoplasm: drug effects
KW  - Cell Line, Tumor
KW  - Apoptosis Regulatory Proteins: metabolism
KW  - Apoptosis Regulatory Proteins: genetics
KW  - Gene Expression Regulation, Neoplastic: drug effects
KW  - Neoplastic Stem Cells: metabolism
KW  - Neoplastic Stem Cells: pathology
KW  - Neoplastic Stem Cells: drug effects
KW  - Brain Neoplasms: pathology
KW  - Brain Neoplasms: genetics
KW  - Brain Neoplasms: metabolism
KW  - Brain Neoplasms: drug therapy
KW  - Membrane Proteins: metabolism
KW  - Membrane Proteins: genetics
KW  - Proto-Oncogene Proteins: metabolism
KW  - Proto-Oncogene Proteins: genetics
KW  - Cell Proliferation: drug effects
KW  - DNA Modification Methylases: metabolism
KW  - DNA Modification Methylases: genetics
KW  - Tumor Suppressor Proteins: metabolism
KW  - Tumor Suppressor Proteins: genetics
KW  - DNA Repair Enzymes: metabolism
KW  - DNA Repair Enzymes: genetics
KW  - MGMT and MMR genes (Other)
KW  - acquired TMZ-resistance (Other)
KW  - glioblastoma (GBM) (Other)
KW  - programmed cell death 10 (PDCD10) (Other)
KW  - stemness (Other)
KW  - Temozolomide (NLM Chemicals)
KW  - Apoptosis Regulatory Proteins (NLM Chemicals)
KW  - PDCD10 protein, human (NLM Chemicals)
KW  - Membrane Proteins (NLM Chemicals)
KW  - Proto-Oncogene Proteins (NLM Chemicals)
KW  - DNA Modification Methylases (NLM Chemicals)
KW  - MGMT protein, human (NLM Chemicals)
KW  - Tumor Suppressor Proteins (NLM Chemicals)
KW  - DNA Repair Enzymes (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39273014
C2  - pmc:PMC11394141
DO  - DOI:10.3390/cells13171442
UR  - https://inrepo02.dkfz.de/record/293309
ER  -