Melatonin Induces PERK‐ATF4 Unfolded Protein Response and Apoptosis in Human Choriocarcinoma Cells
Bibliographic record
Abstract
Melatonin, an indolamine primarily recognized for regulating circadian rhythms, has also demonstrated notable antitumoral properties. Melatonin induces endoplasmic reticulum (ER) stress, modulates autophagy, and promotes apoptosis in various tumors, including gastric, ovarian, cervical, oral tongue, colorectal, renal, hepatic, and bladder cancer. In placental choriocarcinoma, melatonin reduces cell viability and induces apoptosis by inhibiting autophagy and disrupting the mitochondrial membrane potential. However, its effects on ER stress and the unfolded protein response (UPR) pathway remain unexplored. It is hypothesized here that the proapoptotic effects of melatonin in choriocarcinoma cells occur through the activation of the UPR pathway. The factors implicated in the UPR (PERK, IRE1ɑ, ATF6, GRP78, ATF4, CHOP, P-eIF2α) pathways were evaluated by Western blot, RT-qPCR, and flow cytometry in BeWo (human choriocarcinoma) cells treated with or without melatonin (1 mM). Melatonin significantly increased protein levels of GRP78 (p = 0.0329), IRE1α (p = 0.0394), p-eIF2α (p = 0.0439), ATF4 (p = 0.0267), CHOP (p = 0.0379), Bax and cleaved PARP but did not affect TRAF2 and NFkB protein levels nor XBP1 mRNA splicing. PERK knockdown, via siRNA, prevented the rise in GRP78, p-eIF2α/eIF2α, and ATF4 levels by melatonin. Additionally, melatonin increased early apoptosis in BeWo cells (p = 0.0371) and PERK knockdown increased the susceptibility of BeWo cells to apoptosis when treated with tunicamycin (p = 0.0359), suggesting that ER stress plays a role in BeWo cell survival. This study demonstrates that melatonin activates the PERK-ATF4-P-eIF2α-CHOP pathway and induces early apoptosis in BeWo cells, while PERK deficiency compromises cell survival under ER stress. Our findings suggest that modulating PERK-UPR signaling with melatonin could present a promising therapeutic strategy for cancer, including placental choriocarcinoma.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".