Tamoxifen inhibits cell proliferation by impaired glucose metabolism in gallbladder cancer

Abstract

Gallbladder cancer (GBC) is the leading malignancy of biliary system showing refractory chemoresistance to current first-line drugs. Growing epidemiological evidences have established that the incidence of GBC exhibits significant gender predominance with females two-threefold higher than males, suggesting oestrogen/oestrogen receptors (ERs) signalling might be a critical driver of tumorigenesis in gallbladder. This study aims to evaluate the antitumour activity of tamoxifen (TAM), a major agent of hormonal therapy for breast cancer, in preclinical GBC model. Quantitative real-time PCR was used to investigate mRNA levels. Protein expression was measured by immunohistochemistry and Western blot. Glycolytic levels were measured by glucose consumption and lactic acid measurement. The antitumour activity of TAM alone or with cisplatin was examined with CCK8 assay, colony formation, flow cytometry and in vivo models. The results revealed that ERɑ expression was higher in GBC tissues and predicted poor clinical outcomes. TAM was showed effective against a variety of GBC cell lines. Mechanical investigations revealed that TAM enabled potent reactive oxygen species (ROS) production by reduced nuclear factor Nrf2 expression and its target genes, leading to the activation of AMPK, which subsequently induced impaired glycolysis and survival advantages. Notably, TAM was demonstrated to sensitize GBC cells to cisplatin (CDDP) both in vitro and in vivo. In agreement with these findings, elimination of oestrogens by ovariectomy in nude mice prevented CDDP resistance. In summary, these results provide basis for TAM treatment for GBC and shed novel light on the potential application of endocrine therapy for patients with GBC.

Hyperglycemia and Chemoresistance in Breast Cancer: From Cellular Mechanisms to Treatment Response

“…Also, Huang et al. recently reported that tamoxifen inhibits the proliferation of gallbladder cancer cells by impairing glucose metabolism ( 52 ). It is known that the occurrence of gall bladder cancer may be related to estrogen receptors suggesting a potential link with the effects of tamoxifen.…”

Bortezomib‐Encapsulated Dual Responsive Copolymeric Nanoparticles for Gallbladder Cancer Targeted Therapy

“…To formulate ES‐NP (BTZ; Ce6) and encapsulate drugs, BTZ and Ce6 were loaded into the hydrophobic core and self‐assembled with the hydrophilic shell. Due to the high ER expression in GBC (Figure S2 , Supporting Information), the surface‐exposed estrone in the hydrophilic chain act as a tumor‐targeting ligand, [ 10 , 11 , 16 ] whereas the internally packed DA in the hydrophobic chain serves as an ionizable moiety for pH sensitivity. [ 17 ] The use of hydroxyl group as a pH‐sensitive ionizable link between the encapsulated drugs ensures targeted drug delivery at acidic TME, thus lowering drug concentration and avoiding unwanted adverse effects.…”

“…ES‐NP (BTZ; Ce6) has various advantages in cancer therapy. For instance, ES acted as a tumor‐targeting ligand in GBC with relatively high ER expression, [ 10 , 11 ] to help nanoparticles rapidly enter the cells and accumulate near the nucleus via ES‐mediated endocytosis or tissue‐specific interactions. [ 12 ] The acidic TME can also be exploited by tumor‐pH‐sensitive nanoparticles for controlled drug release.…”

Inhibition of AMPK/PFKFB3 Mediated Glycolysis Synergizes with Penfluridol to Suppress Gallbladder Cancer Growth

“…In GBCs, glycolysis is a crucial process to support tumor initiation and progression, which could be developed for cancer therapy [19,20]. For instance, the anti-estrogen drug, tamoxifen, suppressed GBC viability by impairing glycolysis [21]. LncRNA PVT1 could modulate glycolysis by regulating miR-143-HK2 to promote GBC growth [19].…”