Glioma-astrocyte connexin43 confers temozolomide resistance through activation of the E2F1/ERCC1 axis
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Published on: February 16, 2015
Yanping Gui1, Hongkun Qin1, Xinyu Zhang1
1School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P.R. China.
Background:
Glioma is the most prevalent and lethal tumor of the central nervous system. Routine treatment with temozolomide (TMZ) would unfortunately result in inevitable recurrence and therapy resistance, severely limiting therapeutic efficacy. Tumor-associated astrocytes (TAAs) are key components of the tumor microenvironment and increasing evidence has demonstrated that aberrant expression of connexin43 (Cx43) was closely associated with glioma progression and TMZ resistance. However, the specific role of Cx43 in mediating TMZ resistance through glioma and astrocyte interactions has not been fully explored.
Methods:
The expression and prognostic value of Cx43 were evaluated in tumor samples and clinical databases. ShRNA-medicated knockdown and Gfap-Cre Cx43flox/flox gene mouse were used to assess the role and functional significance of Cx43 in vitro and in vivo. Moreover, we performed mass spectrometry analysis, chromatin immunoprecipitation, and other biochemical assays to define the molecular mechanisms by which Cx43 promotes TMZ resistance.
Results:
We confirmed that the upregulation of Cx43 expression between TAAs and glioma cells contributed to TMZ resistance and tumor recurrence. Genetic knockdown or pharmacological inhibition of Cx43 enhanced TMZ-induced cytotoxicity. Mechanistically, elevated Cx43 expression induced β-catenin accumulation at the cell surface of glioma cells, suppressing T-cell factor/lymphoid enhancer-binding factor transcription. This led to impaired miR-205-5p expression and subsequent activation of the E2F1/ERCC1 axis, which eventually led to chemoresistance.
Conclusions:
Our study reveals a novel regulatory mechanism in which the Cx43/miR-205-5p/E2F1/ERCC1 axis contributes to TMZ resistance in glioma. These findings further highlight the potential of targeting Cx43 as a therapeutic strategy in glioma.
Insights
Connexin43 (Cx43) upregulation in glioma promotes temozolomide (TMZ) resistance by altering the tumor microenvironment. Targeting Cx43 offers a potential therapeutic strategy for improving glioma treatment outcomes.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Research
Background:
- Glioma is a deadly brain tumor with limited treatment options.
- Temozolomide (TMZ) resistance and tumor recurrence are major challenges in glioma therapy.
- Tumor-associated astrocytes (TAAs) and connexin43 (Cx43) are implicated in glioma progression and TMZ resistance.
Purpose of the Study:
- To investigate the role of Cx43 in mediating TMZ resistance in glioma.
- To elucidate the molecular mechanisms by which Cx43 contributes to chemoresistance.
- To explore Cx43 as a potential therapeutic target for glioma.
Main Methods:
- Cx43 expression and prognostic value analyzed in clinical samples and databases.
- Cx43 function assessed using knockdown and knockout mouse models (in vitro and in vivo).
- Molecular mechanisms investigated via mass spectrometry, ChIP, and biochemical assays.
Main Results:
- Upregulated Cx43 in TAAs and glioma cells correlated with TMZ resistance and recurrence.
- Cx43 inhibition (genetic or pharmacological) sensitized glioma cells to TMZ.
- Cx43 promotes chemoresistance by upregulating the Cx43/miR-205-5p/E2F1/ERCC1 axis.
Conclusions:
- Cx43 plays a critical role in mediating TMZ resistance in glioma through a novel molecular pathway.
- Targeting Cx43 presents a promising therapeutic avenue for overcoming chemoresistance in glioma patients.
