Ubiquitin-Activating Enzyme E1 Inhibition Caused Acute Leukemia Cell Apoptosis By Affecting CHOP Pathway
Bibliographic record
Abstract
Abstract Background: The ubiquitin proteinase system is involved in the pathogenesis of blood malignant tumors. Preliminary study of our group found that increased serum ubiquitin activase E1 (UBE1) fragment were in newly diagnosed and refractory & relapsed acute myeloid leukemia (AML), and its relative intensity was negatively correlated with AML's remission process and prognosis. The inhibition of UBE1 activity can promote AML cell apoptosis and may be related to the mechanism of endoplasmic reticulum stress. The current study is to clarify the role and mechanism of endoplasmic reticulation-derived transcription factor CHOP in apoptosis of leukemia cells induced by inhibiting ubiquitin activase E1 (UBE1) activity. Methods: UBE1-shRNA lentivirus carrier and CHOP-siRNA plasmid co-infected leukemia cells (U937, K562, NB4, THP-1). The protein expression of antiapoptosis molecules, endoplasmic reticulum stress protein and death receptors (Bcl-2, TRB3, ERO1α, DR5 and Bax) were detected by Western Blot. MTT and flow cytometry were used to detect cell proliferation inhibition and apoptosis. The model of leukemia cell bearing nude mouse was constructed. UBE1-shRNA and/or CHOP-siRNA were injected into the tumor. The tumor size, lifetime changes and tumor pathological changes were observed. Western Blot and RT-PCR were used to detect endoplasmic reticulum stress molecules and apoptosis molecules. Results: Infection of UBE1-shRNA significantly inhibited proliferation of leukemia cells (U937, K562, NB4, THP-1), while the inhibition of UBE1-shRNA and CHOP-siRNA co-transfected leukemia cells was decreased (p=0.032). The apoptosis rate in UBE1-shRNA leukemia cells was lower than that in UBE1-shRNA and CHOP-siRNA co-transfected leukemia cells (p=0.026). UBE1-shRNA can reduce the expression of apoptosis molecule Bcl-2 and increase the expression of TRB3, ERO1α, death receptor DR5, Bax protein. CHOP-siRNA can increase the expression of Bcl-2 in leukemia cells and reduce the expression of TRB3, ERO1α, death receptor DR5 and Bax protein. shRNA-UBE1 inhibited the leukemia cell xenograft, while siRNA-CHOP reversed the growth inhibition of shRNA-UBE1 on leukemia cell xenograft (p=0.002). A larger number of leukemia cells were degenerative necrosis in the UBE1-shRNA group comparing with the UBE1-shRNA and siRNA-CHOP co-transfected groups (p=0.023), and damaged membrane, different sizes, blurred outline, and nuclear pyknosis and karyorrhexis could be observed. The average survival time of mice with co-transfection of shRNA-UBE1 and siRNA-CHOP was shorter than the average survival time of mice with shRNA-UBE1 (p=0.016). Compared with the shRNA-UBE1 group, there was no difference in expression of endoplasmic reticulum stress molecules in co-transfection of UBE1-shRNA and siRNA-CHOP group, but TRB3, ERO1α, DR5, Bax expression were decreased, and Bcl-2 was increased (p<0.05). Conclusion: The inhibition of UBE1 activity can induce AML cell apoptosis by endoplasmic reticulum stress CHOP pathway. It will provide new clues for the treatment of acute myeloid leukemia. Disclosures: No relevant conflicts of interest to declare. Disclosures No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".