Authors
Yuxin Wang, Enkui Zhang, Rui Ma, Weikang Liu, Qi Wang, Jun Zhang, Yinmo Yang, Yongsu Ma, Xiaodong Tian
Published in
Cellular oncology (Dordrecht, Netherlands). Jul 06, 2026. Epub Jul 06, 2026.
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with profound metabolic rewiring and resistance to therapy. Sodium-glucose cotransporter 2 (SGLT2) regulates glucose uptake, but its role in PDAC remains unclear.
SGLT2 expression was analyzed in clinical samples and public datasets. PDAC cell lines were subjected to genetic knockdown or canagliflozin (CANA) treatment to assess proliferation, migration, apoptosis, and glucose metabolism. Mechanistic studies investigated AMPK-ULK1 signaling, autophagy dynamics, oxidative stress, and EGFR signaling. Xenograft models were used to assess in vivo efficacy.
SGLT2 was upregulated in PDAC and associated with poor prognosis. SGLT2 inhibition suppressed proliferation and migration while promoting apoptosis. Mechanistically, CANA induced ATP deficiency and initiated autophagy, but concurrently impaired autophagosome-lysosome fusion. This dual effect led to autophagic flux blockade, resulting in excessive ROS accumulation, mitochondrial dysfunction, and apoptosis. Inhibition of AMPK reduced ROS levels, while ROS scavenging partially rescued mitochondrial damage and cell death. Notably, SGLT2 inhibition enhanced sensitivity to EGFR-targeted therapy, producing synergistic anti-tumor effects in vitro and in vivo.
SGLT2 maintains metabolic and autophagic homeostasis in PDAC. Its inhibition induces metabolic stress, autophagic flux blockade, and ROS-driven mitochondrial apoptosis. In addition, targeting SGLT2 sensitizes tumors to EGFR-targeted therapy, offering a novel combinatorial strategy.
PMID:
42410080
Bibliographic data and abstract were imported from PubMed on 07 Jul 2026.
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