Tamoxifen modulates nutrition deprivation-induced ER stress through AMPK-mediated ER-phagy in breast cancer cells

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Abstract
Purpose Rapid proliferation and nutrition starvation in the tumor microenvironment pose significant challenges to cellular protein homeostasis. The accumulation of misfolded proteins in the endoplasmic reticulum lumen induces stress on cells and causes irreversible damage to cells if unresolved. Emerging reports emphasize the influence of the tumor microenvironment on therapeutic molecule efficacy and treatment outcomes. Hence, we aimed to understand the influence of tamoxifen on the cellular adaptation to endoplasmic reticulum stress during metabolic stress in breast cancer cells. Methods Nutrition deprivation induces endoplasmic reticulum stress (ER stress), and the unfolded protein response (UPR) in breast cancer cells was confirmed by a Thioflavin B assay and western blotting. Tamoxifen-indued ER-phagy was studied using an MCD assay, confocal microscopy, and western blotting. Results Nutrition deprivation induces ER stress in breast cancer cells. Interestingly, tamoxifen modulates the nutrition deprivation-induced endoplasmic reticulum stress through enhancing the selective ER-phagy, a specialized autophagy. The tamoxifen-induced ER-phagy is mediated by AMPK activation. The pharmacological inhibition of AMPK blocks tamoxifen-induced ER-phagy and tamoxifen modulatory effect on ER stress during nutrition deprivation. Conclusion Tamoxifen modulates ER stress by inducing ER-phagy through AMPK, thereby, may support breast cancer cell survival during nutrition deprivation conditions.
Funding Information
  • Indian Council of Medical Research (67/06/2022-DDI/BMS and 5/7/1745/CH/Adhoc/RBMCH‐2021)
  • Department of Science and Technology, Ministry of Science and Technology, India (CRG/2022/004934)

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