Interplay between ER stress and DNA repair pathways in solid tumors under hypoxia

Area of Science:

• Oncology
• Molecular Biology
• Cellular Stress Response

Background:

• Solid tumors frequently exhibit a hypoxic microenvironment, driving tumor progression and therapeutic resistance.
• Hypoxia activates HIF1α, influencing metabolic reprogramming and angiogenesis.
• Hypoxia compromises endoplasmic reticulum (ER) function, leading to ER stress (ERS) and the unfolded protein response (UPR).
• Hypoxic stress also induces DNA damage and genomic instability via replication stress and DNA damage repair (DDR) pathway dysregulation.

Purpose of the Study:

• To review the mechanisms of UPR sensor and DDR component interplay under hypoxia.
• To understand how this crosstalk influences cancer cell fate.
• To identify potential therapeutic targets arising from these interactions.

Main Methods:

• Literature review focusing on molecular mechanisms.
• Analysis of the interplay between UPR and DDR pathways in cancer.
• Examination of cellular responses to hypoxic stress.

Main Results:

• UPR sensors and DDR components are mechanistically linked under hypoxic conditions.
• This crosstalk significantly influences cancer cell fate, including survival and proliferation.
• The interplay between UPR and DDR creates unique cellular vulnerabilities.

Conclusions:

• Elucidating the crosstalk between UPR and DDR in hypoxia is crucial for understanding tumor evolution and metastasis.
• Targeting the vulnerabilities arising from this interplay offers promising therapeutic intervention strategies for solid tumors.