Related Experiment Video
Updated: Jul 1, 2025
10:36
Measurements of Physiological Stress Responses in C. Elegans
Published on: May 21, 2020
13.9K
ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway
Chang-Hoon Lim1,2, Xue-Quan Fang1,2, Hyeji Kang1
1Department of Medicinal Biosciences, College of Biomedical & Health Science, Konkuk University, 268, Chungwon-daero, Chungju 27478, Chungbuk, Republic of Korea.
International Journal of Molecular Sciences
|March 13, 2024
Summary
Ubiquitin-specific protease 7 inhibitors (USP7i) can cause chemoresistance in cancer cells. Targeting the endoplasmic reticulum stress-PERK pathway overcomes this resistance, enhancing USP7i
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Ubiquitin-specific protease 7 inhibitors (USP7i) represent a novel anticancer drug class.
- Cancer cells can develop chemoresistance, leading to poor patient outcomes.
- Mechanisms of USP7i resistance and strategies to overcome it remain largely unexplored.
Purpose of the Study:
- To investigate chemoresistance mechanisms in cancer cells treated with USP7i.
- To identify potential therapeutic strategies to overcome USP7i resistance.
Main Methods:
- Generation of human cancer cells with acquired resistance to USP7i.
- Gene expression profiling to identify upregulated pathways in resistant cells.
- Biochemical assays to elucidate signaling pathways involved in resistance.
Main Results:
- USP7i-resistant cells exhibited upregulated heat stress response (HSR) and unfolded protein response (UPR) genes.
- USP7i treatment induced heat shock transcription factor 1 (HSF1) phosphorylation via the ER stress-PERK pathway.
- Inhibition of HSF1 and PERK sensitized resistant cells to USP7i-induced cytotoxicity.
Conclusions:
- The endoplasmic reticulum (ER) stress-PERK axis is a key mechanism driving chemoresistance to USP7i.
- Inhibiting PERK presents a promising strategy to enhance the efficacy of USP7i in cancer therapy.
Related Concept Videos
03:03mTOR Signaling and Cancer Progression
3.8K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.8K
01:31Regulation of the Unfolded Protein Response
2.4K
Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.4K
02:23Abnormal Proliferation
4.5K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.5K
01:19Interactions Between Signaling Pathways
6.3K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.3K
02:56Treatment Resistant Cancers
3.3K
Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.3K
02:37DNA Damage can Stall the Cell Cycle
9.1K
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.1K