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iASPP suppression mediates terminal UPR and improves BRAF-inhibitor sensitivity of colon cancers
Shanliang Zheng1, Xingwen Wang1, Hao Liu1
1School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, 150001, China.
Abstract:
Unfolded protein response (UPR) signaling is activated under endoplasmic reticulum (ER) stress, an emerging cancer hallmark, leading to either adaptive survival or cell death, while the mechanisms underlying adaptation-death switch remain poorly understood. Here, we examined whether oncogene iASPP regulates the switch and how the mechanisms can be used in colon cancer treatment. iASPP is downregulated when cells undergo transition from adaptation to death during therapy-induced ER stress. Blocking iASPP's downregulation attenuates stress-induced cell death. Mechanistically, Hu-antigen R (HuR)-mediated stabilization of iASPP mRNA and subsequent iASPP protein production is significantly impaired with prolonged ER stress, which facilitates the degradation of GRP78, a key regulator of the UPR, in the cytosol. Because iASPP competes with GRP78 in binding the ER-resident E3 ligase RNF185, and tips the balance in favor of cell death. Positive correlation between the levels of HuR, iASPP, and GRP78 are detectable in colon cancer tissues in vivo. Genetic inhibition of iASPP/GRP78 or chemical inhibition of HuR not only inhibits tumor growth, but also sensitizes colon cancer cells' responses to BRAF inhibitor-induced ER stress and cell death. This study provides mechanistic insights into the switch between adaptation and death during ER stress, and also identifies a potential strategy to improve BRAF-inhibitor efficiency in colon cancers.
Insights
Oncogene iASPP regulates the switch between cell survival and death during endoplasmic reticulum (ER) stress. Inhibiting iASPP enhances colon cancer cell death, improving BRAF inhibitor therapy.
Area of Science:
- Cellular biology
- Cancer research
- Molecular mechanisms
Background:
- Endoplasmic reticulum (ER) stress triggers the unfolded protein response (UPR), influencing cancer cell survival or death.
- The precise mechanisms governing the adaptation-death switch in UPR remain unclear.
- Oncogene iASPP's role in this switch and its therapeutic potential in colon cancer require investigation.
Purpose of the Study:
- To investigate the role of oncogene iASPP in regulating the adaptation-death switch during ER stress.
- To elucidate the molecular mechanisms by which iASPP influences ER stress-induced cell fate.
- To explore the therapeutic implications of targeting iASPP in colon cancer treatment.
Main Methods:
- Examined iASPP expression during therapy-induced ER stress.
- Investigated the interaction between iASPP, Hu-antigen R (HuR), GRP78, and RNF185.
- Analyzed HuR-mediated mRNA stabilization and protein degradation pathways.
- Correlated HuR, iASPP, and GRP78 levels in colon cancer tissues.
- Assessed the effects of genetic and chemical inhibition on tumor growth and drug sensitivity.
Main Results:
- iASPP is downregulated during the transition from adaptation to cell death under ER stress.
- Blocking iASPP downregulation protects cells from ER stress-induced death.
- Prolonged ER stress impairs HuR-mediated iASPP stabilization, promoting GRP78 degradation.
- iASPP competes with GRP78 for RNF185 binding, favoring cell death.
- Positive correlations between HuR, iASPP, and GRP78 levels were observed in colon cancer tissues.
- Inhibition of iASPP/GRP78 or HuR suppressed tumor growth and sensitized cells to BRAF inhibitors.
Conclusions:
- iASPP acts as a critical regulator of the adaptation-death switch in response to ER stress.
- The HuR/iASPP/GRP78 axis provides a mechanistic link between ER stress and cell fate determination.
- Targeting this axis, particularly HuR, offers a promising strategy to enhance BRAF inhibitor efficacy in colon cancer.
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