bims-meluca 2026-04-05 papers

Cell Death Dis. 2026 Mar 28.

REDD1/DDIT4 counteracts endoplasmic reticulum stress-induced apoptosis by controlling the expression of death receptor TRAILR2/DR5 in cancer cells.

Rocío Mora-Molina, Younes El Yousfi, Cathrin Hagenlocher, Francisco Javier Fernández-Farrán, Markus Rehm, Carmen Palacios, Maria A Christophorou, Abelardo López-Rivas.

Regulated in development and DNA damage response-1 (REDD1/DDIT4) is induced in response to environmental stress to restrain the mechanistic target of rapamycin complex 1 (mTORC1) signaling as an adaptive strategy to restore cellular homeostasis. Interestingly, REDD1/DDIT4 expression is upregulated in several tumor types including colorectal cancer, suggesting it may have a role in tumourigenesis. Here, we report that activating transcription factor 4 (ATF4)-dependent REDD1/DDIT4 expression is required for survival of colon tumor cells undergoing endoplasmic reticulum (ER) stress through the modulation of TRAILR2/DR5 gene expression. Our findings further demonstrate that resistance to ER stress-induced apoptosis in multicellular tumor spheroids (MCTS) is associated with constitutive expression of REDD1/DDIT4 and diminished mTORC1 activity. CRISPR/Cas9-mediated deletion of REDD1/DDIT4 markedly increases TRAILR2/DR5 expression and enhances apoptosis in spheroids exposed to ER stress. Interestingly, RNA sequencing analysis reveals that the loss of the transcriptional regulator EVI-1/MECOM in cells deficient in REDD1/DDIT4 amplifies the ER stress-induced upregulation of TRAILR2/DR5, leading to enhanced apoptosis. In summary, our findings underscore the crucial role of REDD1/DDIT4 in regulating TRAILR2/DR5-induced caspase-8 activation and apoptosis under chronic ER stress, by inhibiting mTORC1 activity and promoting EVI-1/MECOM-mediated suppression of TRAILR2/DR5 gene expression.

DOI: https://doi.org/10.1038/s41419-026-08648-7

FASEB J. 2026 Apr 15. 40(7): e71726

Lactate Facilitates the Survival and Invasion of Pancreatic Cancer Cells Under Glucose Deprivation.

Fan Wang, Ping Hu, Shengbo Han, Ya Zhang, Yang Li, Wenfeng Zhuo, Yong Zhao, Yan Huang, Guozheng Lv, Hongda Wang, Gang Zhao.

Lactate has been considered as a tumor-promoting metabolite, however, its functional roles in pancreatic cancer (PC) have not yet been fully elucidated. Here, we explored the roles of lactate on the proliferation and invasion of PC cells under glucose deprivation. We found that lactate enhanced PC cells' proliferation and invasion under glucose deprivation, but not in normal conditions. The Cancer Genome Atlas (TCGA) Pancreatic Adenocarcinoma (PAAD) dataset showed that monocarboxylic acid transporter 1 (MCT1), a lactate transporter, was overexpressed and correlated with poor prognosis in PC patients. Additionally, knockdown or inhibition of MCT1 distinctively attenuated lactate-induced proliferation and invasion of PC cells under glucose deprivation by suppressing their tricarboxylic acid (TCA) cycle. Importantly, the MCT1 inhibitor AZD3965 synergistically enhanced the anticancer effects of the glycolysis inhibitor 2-DG. Taken together, our results demonstrate that MCT1-mediated lactate influx sustains PC proliferation under glucose starvation, and combined inhibition of MCT1 and glycolysis could be leveraged for treatment of PC.

Keywords: MCT1; TCA; lactate; metastasis; proliferation

DOI: https://doi.org/10.1096/fj.202503162RR

Front Endocrinol (Lausanne). 2026 ;17 1797525

Metformin increases glycolysis and the stress-induced cytokine GDF15 but not FGF21 in humans.

Kristoffer J Kolnes, Pauline M Møller, Rikke Kruse, Mette Marie H Christensen, Rasmus Kjøbsted, Martin Hey-Mogensen, Birgitte Andersen, Aase Handberg, Kurt Højlund.

Background: Metformin lowers glucose by acting on the liver and the gastrointestinal tract and may reduce body weight by increasing circulating levels of the stress-induced cytokine GDF15. The tissue responsible for the release of GDF15 and whether this is paralleled by the induction of another, mainly liver derived, stress-responsive cytokine, FGF21, remains unclear.
Objective: We examined the effect of metformin on GDF15 and FGF21 in humans and in intestinal cells in vitro.
Methods: In a randomized, cross-over trial, 34 healthy individuals completed a 42-h fast twice, either with or without prior treatment with metformin for a week. Glucose metabolism was assessed using [3-3H]-glucose and indirect calorimetry and blood samples were drawn for the analysis of plasma metformin and serum GDF15 and FGF21. The effects of metformin on the expression and secretion of GDF15 and FGF21, and on mitochondrial respiration and glycolysis were examined in human intestinal epithelial cells (Caco-2).
Results: Metformin increased glucose utilization (p=8.9x10-13) due to increased glycolysis (p=7.6x10-13) in vivo. This was accompanied by increased serum GDF15 (1004±61 vs 607±89 ng/ml; p<0.001), whereas serum FGF21 (146±30 vs 156±29 ng/ml; p=0.65) was unaltered. The change in serum GDF15 did not correlate with plasma metformin levels. In vitro, metformin markedly increased mRNA levels and secretion of GDF15, whereas FGF21 levels were not detectable in Caco-2 cells or media. Moreover, metformin dose-dependently inhibited mitochondrial respiration and increased glycolysis in vitro.
Conclusions: The metformin-induced increase in serum GDF15, but not the liver-derived FGF21, in humans is consistent with the actions of metformin in human intestinal cells in vitro. These findings corroborate with recent studies demonstrating the gastrointestinal tract is an important site of metformin action.
Clinical Trial Registration: ClinicalTrials.gov, Identifier NCT01400191.

Keywords: FGF21; GDF15; glycolysis; intestine; metformin; mitochondrial respiration

DOI: https://doi.org/10.3389/fendo.2026.1797525

Support Care Cancer. 2026 Apr 01. pii: 395. [Epub ahead of print]34(4):

Subcutaneous adipose tissue loss as an early indicator of cancer cachexia in unresectable pancreatic cancer.

Mariko Ohara, Osamu Inatomi, Hiroto Inoue, Noriaki Yamashita, Shuhei Shintani, Takayuki Imai, Hiroshi Matsumoto, Masashi Ohno, Hidenori Kimura, Atsushi Nishida, Takuji Iwashita.

PURPOSE: Body-composition indices beyond body mass index (BMI) are increasingly being investigated as prognostic cancer markers. In pancreatic cancer, the prognostic relevance of skeletal muscle and adipose tissue compartments remains uncertain, with studies yielding inconsistent findings. We examined whether early on-treatment changes in subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle index (SMI) are associated with unresectable pancreatic cancer prognosis.
METHODS: This retrospective cohort study comprised patients with unresectable pancreatic cancer who received chemotherapy between 2019 and 2024. Baseline and 3-month computed tomography (CT) scans at L3 were analyzed to quantify SAT, VAT, and SMI, calculating percent changes (Δ%). A 3-month landmark approach was applied to survival analyses. Associations with overall survival (OS) were examined using Cox models; discrimination with receiver operating characteristic curves; and survival differences using Kaplan-Meier and log-rank tests.
RESULTS: Sixty-nine patients were included (median age, 71 years; median OS, 12.0 months). Greater preservation of SAT Δ% was associated with reduced mortality risk (HR per tertile step, 0.64; 95% confidence interval, 0.44-0.94), whereas VAT and SMI changes were not significant. SAT Δ% achieved the highest AUC for classifying short- vs long-term survival (0.73) compared with VAT (0.65) and SMI (0.52). The Kaplan-Meier analysis showed significant separation between extreme SAT tertiles (p = 0.02).
CONCLUSION: Early SAT loss was more strongly associated with poor prognosis than concurrent VAT or SMI changes. Serial assessment of SAT on routine CT may enhance early risk stratification in unresectable pancreatic cancer.

Keywords: Pancreatic neoplasms; Prognosis; Sarcopenia; Subcutaneous fat

DOI: https://doi.org/10.1007/s00520-026-10614-0