Resveratrol Specifically Kills Cancer Cells by a Devastating Increase in the Ca2+ Coupling Between the Greatly
Corina T Madreiter-Sokolowski1, Benjamin Gottschalk, Warisara Parichatikanond
1Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
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.
Insights
Resveratrol and piceatannol induce cancer cell death by disrupting calcium regulation in cancer cells, not normal cells. This occurs due to enhanced ER-mitochondria connections, leading to calcium overload and cell death.
Area of Science:
- Cell biology
- Molecular oncology
- Biochemistry
Background:
- Resveratrol and piceatannol induce cancer cell death.
- Mechanisms of cancer specificity remain unclear.
- Known actions include ATP synthase inhibition and ROS level changes.
Purpose of the Study:
- Elucidate the molecular basis of cancer-specific cell death induced by resveratrol and piceatannol.
- Investigate the role of calcium and ATP in polyphenol-induced cancer cell death.
Main Methods:
- Utilized cancer cell lines (EA.hy926, HeLa) and somatic cells (HUVEC).
- Assessed cell viability and caspase 3/7 activity.
- Measured intracellular calcium and ATP levels using fluorescence microscopy and genetically-encoded sensors.
- Analyzed mitochondria-ER junctions via super-resolution microscopy.
Main Results:
- Resveratrol and piceatannol selectively triggered death in cancer cells.
- Enhanced mitochondrial calcium uptake exclusively in cancer cells.
- Reduced SERCA activity due to decreased mitochondrial ATP levels.
- Increased mitochondria-ER tethering in cancer cells enhanced MCU/Letm1-dependent calcium uptake.
- Knockdown of MCU and Letm1 prevented polyphenol-induced cancer cell death.
Conclusions:
- Cancer cells exhibit increased susceptibility to resveratrol/piceatannol due to enhanced ER-mitochondria tethering.
- This tethering facilitates SERCA activity reduction, leading to mitochondrial calcium overload and cancer cell death.
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