Decrease of Nibrin expression in chronic hypoxia is associated with hypoxia-induced chemoresistance in some brain...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Tumor hypoxia is a known cause of treatment resistance in solid tumors.
• Mechanisms of hypoxia-induced resistance are well-studied in adult brain tumors but less so in pediatric brain tumors.
• Medulloblastoma (MB) is the most common malignant pediatric brain tumor.

Purpose of the Study:

• To investigate the impact of hypoxia on the sensitivity of medulloblastoma cells to chemotherapy and radiotherapy.
• To elucidate the molecular mechanisms underlying hypoxia-induced treatment resistance in pediatric brain tumors.

Main Methods:

• Utilized medulloblastoma (D283-MED, MEB-Med8A) and glioblastoma (U87MG) cell lines.
• Employed cell survival assays, cell cycle analysis, protein expression studies, and DNA damage assessments.
• Conducted transcriptomic micro-array analysis to assess global gene expression changes under hypoxic conditions.

Main Results:

• Chronic hypoxia (5 days) induced chemo- and radioresistance in D283-MED and U87MG cells, while acute hypoxia (24 hours) did not.
• Transcriptomic analysis revealed significant alterations in genes involved in double-strand break (DSB) repair in hypoxic D283-MED cells.
• Down-regulation of Nibrin (NBN) and MRE11, key components of the MRN complex, led to dampened DNA damage signaling (reduced ATM and p53 activation) and enhanced cell survival.
• U87MG cells exhibited dampened p53 activity but employed a DNA damage-independent mechanism for resistance.

Conclusions:

• Demonstrated a novel mechanism of hypoxia-induced resistance in medulloblastoma involving altered DSB repair response.
• Highlighted significant cell-type diversity in hypoxia-induced resistance mechanisms.
• Emphasized the importance of considering individual tumor genetic profiles for developing effective re-sensitization therapeutic strategies.