Resveratrol Specifically Kills Cancer Cells by a Devastating Increase in the Ca2+ Coupling Between the Greatly Tethered Endoplasmic Reticulum and Mitochondria

Abstract

Background/Aims: Resveratrol and its derivate piceatannol are known to induce cancer cell-specific cell death. While multiple mechanisms of actions have been described including the inhibition of ATP synthase, changes in mitochondrial membrane potential and ROS levels, the exact mechanisms of cancer specificity of these polyphenols remain unclear. This paper is designed to reveal the molecular basis of the cancer-specific initiation of cell death by resveratrol and piceatannol. Methods: The two cancer cell lines EA.hy926 and HeLa, and somatic short-term cultured HUVEC were used. Cell viability and caspase 3/7 activity were tested. Mitochondrial, cytosolic and endoplasmic reticulum Ca²⁺ as well as cytosolic and mitochondrial ATP levels were measured using single cell fluorescence microscopy and respective genetically-encoded sensors. Mitochondria-ER junctions were analyzed applying super-resolution SIM and ImageJ-based image analysis. Results: Resveratrol and piceatannol selectively trigger death in cancer but not somatic cells. Hence, these polyphenols strongly enhanced mitochondrial Ca²⁺ uptake in cancer exclusively. Resveratrol and piceatannol predominantly affect mitochondrial but not cytosolic ATP content that yields in a reduced SERCA activity. Decreased SERCA activity and the strongly enriched tethering of the ER and mitochondria in cancer cells result in an enhanced MCU/Letm1-dependent mitochondrial Ca²⁺ uptake upon intracellular Ca²⁺ release exclusively in cancer cells. Accordingly, resveratrol/piceatannol-induced cancer cell death could be prevented by siRNA-mediated knock-down of MCU and Letm1. Conclusions: Because their greatly enriched ER-mitochondria tethering, cancer cells are highly susceptible for resveratrol/piceatannol-induced reduction of SERCA activity to yield mitochondrial Ca²⁺ overload and subsequent cancer cell death.

Mitochondrial Ca2+ dynamics in cells and suspensions

“…At this point, it should be emphasised that in intact cells, the dynamics of mitochondrial Ca 2+ is also controlled indirectly by the rate of Ca 2+ exchanges between the cytoplasm and the ER. Thus, decreasing SERCA activity or increasing IP 3 receptor activity both lead to a faster Ca 2+ increase inside mitochondria . These observations are reproduced by our model for intact cells .…”

Targeting mitochondria‐associated membranes as a potential therapy against endothelial injury induced by hypoxia

“…However, little is known about the role of MAMs in ECs. Administration of MAMs altered the Ca 2+ m influx and production of mROS to regulate endothelial apoptosis upon hypoxia/reoxygenation and resveratrol stimuli . In our study, we demonstrated that increased ER‐mitochondria connections induced by hypoxia enhance Ca 2+ m levels with a decrease in ΔΨ values.…”

Resveratrol Alleviates Inflammatory Responses and Oxidative Stress in Rat Kidney Ischemia-Reperfusion Injury and H2O2-Induced NRK-52E Cells via the Nrf2/TLR4/NF-κB Pathway

“…RSV, a natural polyphenol, has potentially beneficial properties including reducing oxidative stress and decreasing inflammatory responses [9, 33, 34]. To the best of our knowledge, our study is the first to show the involvement of the Nrf2/TLR4 signaling pathway in RSV-mediated protection against renal IRI using in vivo and in vitro models.…”