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Updated: Jan 10, 2026
Generation and Expansion of Primary, Malignant Pleural Mesothelioma Tumor Lines
Published on: April 21, 2022
Characterization of bortezomib-adapted I-45 mesothelioma cells
Lidong Zhang1, James E Littlejohn, Yu Cui
1Section of Surgery Research, Department of Surgery, Texas A & M University Health Science Center College of Medicine and Scott & White Memorial Hospital, Temple, Texas, USA. lidongz@bcm.tmc.edu
Background:
Bortezomib, a proteasome-specific inhibitor, has emerged as a promising cancer therapeutic agent. However, development of resistance to bortezomib may pose a challenge to effective anticancer therapy. Therefore, characterization of cellular mechanisms involved in bortezomib resistance and development of effective strategies to overcome this resistance represent important steps in the advancement of bortezomib-mediated cancer therapy.
Results:
The present study reports the development of I-45-BTZ-R, a bortezomib-resistant cell line, from the bortezomib-sensitive mesothelioma cell line I-45. I-45-BTZ-R cells showed no cross-resistance to the chemotherapeutic drugs cisplatin, 5-fluorouracil, and doxorubicin. Moreover, the bortezomib-adapted I-45-BTZ-R cells had decreased growth kinemics and did not over express proteasome subunit beta5 (PSMB5) as compared to parental I-45 cells. I-45-BTZ-R cells and parental I-45 cells showed similar inhibition of proteasome activity, but I-45-BTZ-R cells exhibited much less accumulation of ubiquitinated proteins following exposure to 40 nm bortezomib. Further studies revealed that relatively low doses of bortezomib did not induce an unfolded protein response (UPR) in the bortezomib-adapted cells, while higher doses induced UPR with concomitant cell death, as evidenced by higher expression of the mitochondrial chaperone protein Bip and the endoplasmic reticulum (ER) stress-related pro-apoptotic protein CHOP. In addition, bortezomib exposure did not induce the accumulation of the pro-apoptotic proteins p53, Mcl-1S, and noxa in the bortezomib-adapted cells.
Conclusion:
These results suggest that UPR evasion, together with reduced pro-apoptotic gene induction, accounts for bortezomib resistance in the bortezomib-adapted mesothelioma cell line I-45-BTZ-R.
Insights
Bortezomib resistance in mesothelioma cells involves evading the unfolded protein response (UPR) and reduced pro-apoptotic gene induction. This adaptation allows cancer cells to survive bortezomib treatment, impacting therapy effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Bortezomib is a proteasome inhibitor used in cancer therapy.
- Acquired resistance to bortezomib presents a significant clinical challenge.
- Understanding resistance mechanisms is crucial for improving bortezomib efficacy.
Purpose of the Study:
- To characterize the cellular mechanisms underlying bortezomib resistance.
- To develop strategies to overcome bortezomib resistance in cancer.
- To investigate bortezomib resistance in a mesothelioma cell line.
Main Methods:
- Development of a bortezomib-resistant mesothelioma cell line (I-45-BTZ-R) from a sensitive counterpart (I-45).
- Assessment of cross-resistance to other chemotherapeutic agents.
- Analysis of proteasome activity, ubiquitinated protein accumulation, and unfolded protein response (UPR) markers (Bip, CHOP).
- Evaluation of pro-apoptotic protein expression (p53, Mcl-1S, noxa).
Main Results:
- The resistant cell line (I-45-BTZ-R) showed no cross-resistance to cisplatin, 5-fluorouracil, or doxorubicin.
- I-45-BTZ-R cells exhibited reduced growth kinetics and no overexpression of PSMB5.
- These cells displayed less ubiquitinated protein accumulation and evaded UPR induction at lower bortezomib doses.
- Higher bortezomib doses induced UPR and cell death in resistant cells, with no significant induction of p53, Mcl-1S, or noxa.
Conclusions:
- UPR evasion is a key mechanism of bortezomib resistance in this mesothelioma model.
- Reduced induction of pro-apoptotic genes contributes to bortezomib resistance.
- These findings offer insights into overcoming bortezomib resistance in cancer therapy.
