Mechanisms of resveratrol-induced changes in cytosolic free calcium ion concentrations and cell viability in OC2 human oral cancer cells

Hj, Chang; Ct, Chou; Ht, Chang; Wz, Liang; Ty, Hung; Yd, Li; Yc, Fang; Cc, Kuo; Dh, Kuo; Shieh, Pochuen; Cr, Jan

doi:10.1177/0960327114537536

Cited by 14 publications

(11 citation statements)

References 34 publications

(52 reference statements)

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“…To study the functional effects of WNT5A‐induced PKC activation we have in the present study used two conventional PKC inhibitors, GF109203X (inhibitor of PKC α, β1, β2, and γ) and Go 6983 (inhibitor of PKC α, β, γ, δ, and ζ). These inhibitors have previously been used in OSCC cells . In the present study, both PKC inhibitors significantly repressed rWNT5A‐induced OSCC cell migration.…”

Section: Discussionsupporting

confidence: 58%

See 1 more Smart Citation

Migration and invasion of oral squamous carcinoma cells is promoted by WNT5A, a regulator of cancer progression

Prgomet

Axelsson

Lindberg

et al. 2014

J Oral Pathology Medicine

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BACKGROUND: Oral squamous cell carcinoma (OSCC) constitutes 90% of all cancers in the oral cavity, and the prognosis for patients diagnosed with OSCC is still poor. The identification of novel therapeutic targets and prognostic markers for OSCC is therefore essential. Previous studies of OSCC revealed an increased expression of WNT5A in the tumor tissue. However, no functional studies of WNT5A-induced effects in OSCC have been performed. METHODS: Two different OSCC cell lines were used for analysis of WNT5A expression by Western blot, whereas WNT5A-induced responses were analyzed by measuring calcium (Ca 2+ ) signaling, PKC activation, migration and invasion. RESULTS: Despite the lack of WNT5A expression, both cell lines responded to recombinant WNT5A (rWNT5A) with activation of the non-canonical WNT/Ca 2+ /PKC pathway. This effect was ascertained to be mediated by WNT5A by use of the WNT5A antagonist, Box5. To investigate how WNT5A affects tumor progression, rWNT5A-induced alterations in BrdU absorbance (reflecting the number of tumor cells) were analyzed. rWNT5A had no effect on BrdU absorbance but instead promoted tumor cell migration and invasion. These results were confirmed by the use of the WNT5A-mimicking peptide Foxy5, while the rWNT5A-induced migration was blocked by secreted Frizzled-related protein 1 (SFRP1), protein kinase C inhibitors or the intracellular Ca 2+ chelator, MAPT. CONCLUSIONS: These novel data clearly show that WNT5A activates the non-canonical WNT/Ca 2+ /PKC pathway and increases migration and invasion of OSCC cells. This may indicate how an increased WNT5A expression in the tumor tissue is likely to promote progression of OSCC.

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Section: Discussionsupporting

confidence: 58%

“…C). As WNT5A activates protein kinase C (PKC) in OSCC cells (Fig A,B), two conventional PKC pathway inhibitors previously used to inhibit PKC activity in OSCC cells were used to study the role of PKC in WNT5A‐induced SCC25 cell migration. Both PKC inhibitors (1 μM) abolished the migration of SCC25 cells mediated by WNT5A (Fig.…”

Section: Resultsmentioning

confidence: 99%

Migration and invasion of oral squamous carcinoma cells is promoted by WNT5A, a regulator of cancer progression

Prgomet

Axelsson

Lindberg

et al. 2014

J Oral Pathology Medicine

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“…It is well documented that resveratrol and its derivate piceatannol induce cell death exclusively in cancer cells, including human breast cancer cell line MCF-7 [67, 68], human oral cancer cells OC2 [69], human promyelocytic leukemia cells HL-60 [70], human prostate carcinoma cells LNCaP, and HeLa cells [58]. In line with these reports, in the present work the hybrid-cell line EA.hy926 [71] and HeLa [72] were found to be sensitive to resveratrol- and piceatannol-induced cell death as well.…”

Section: Discussionmentioning

confidence: 99%

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

Madreiter‐Sokolowski

Gottschalk

Parichatikanond

et al. 2016

Cell Physiol Biochem

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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.

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“…As reported by others (33), a portion of the calcium response may be contingent upon extracellular calcium. Therefore, the responses to quercetin and resveratrol were measured in the presence and absence of extracellular calcium.…”

Section: Resultsmentioning

confidence: 55%

Natural products induce a G protein-mediated calcium pathway activating p53 in cancer cells

Ginkel

Yan

Bhattacharya

et al. 2015

Toxicology and Applied Pharmacology

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Paclitaxel, etoposide, vincristine and doxorubicin are examples of natural products being used as chemotherapeutics but with adverse side effects that limit their therapeutic window. Natural products derived from plants and having low toxicity, such as quercetin, resveratrol, epigallocatechin gallate and piceatannol, have been shown to inhibit tumor cell growth both in vitro and in pre-clinical models of cancer, but their mechanisms of action have not been fully elucidated, thus restricting their use as prototypes for developing synthetic analogs with improved anti-cancer properties. We and others have demonstrated that one of the earliest and consistent events upon exposure of tumor cells to these less toxic natural products is a rise in cytoplasmic calcium, activating several pro-apoptotic pathways. We describe here a G protein/inositol 1,4,5-trisphosphate pathway (InsP3) in MDA-MB-231 human breast cancer cells that mediates between these less toxic natural products and the release of calcium from the endoplasmic reticulum. Further, we demonstrate that this elevation of intracellular calcium modulates p53 activity and the subsequent transcription of several pro-apoptotic genes encoding PIG8, CD95, PIDD, TP53INP, RRM2B, Noxa, p21 and PUMA. We conclude from our findings that less toxic natural products likely bind to a G protein coupled receptor that activates a G protein-mediated and calcium-dependent pathway resulting selectively in tumor cell death.

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Mechanisms of resveratrol-induced changes in cytosolic free calcium ion concentrations and cell viability in OC2 human oral cancer cells

Cited by 14 publications

References 34 publications

Migration and invasion of oral squamous carcinoma cells is promoted by WNT5A, a regulator of cancer progression

Migration and invasion of oral squamous carcinoma cells is promoted by WNT5A, a regulator of cancer progression

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

Natural products induce a G protein-mediated calcium pathway activating p53 in cancer cells

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