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Quercetin down-regulates signal transduction in human breast carcinoma cells
R L Singhal1, Y A Yeh, N Praja
1Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46202-5200.
Abstract:
Signal transduction activity was markedly elevated in cancer cells as shown by the increased activity of enzymes utilizing 1-phosphatidylinositol, PI (PI 4-kinase and PI-4-phosphate 5-kinase) for the production of the second messenger inositol 1,4,5-trisphosphate, IP3, in rat hepatomas (Cancer Res. 54: 2611;5574, 1994) and in human ovarian and breast carcinoma cells (Life Sci. 55:1487, 1994). Quercetin, a flavonoid, in human breast carcinoma MDA-MB-435 cells produced growth inhibition (IC50 = 55 microM) and cytotoxicity (LC50 = 26 microM). Quercetin inhibited PI kinase activity in extracts of breast carcinoma cells (IC50 = 6 microM) and in cultured cells (IC50 = 10 microM) with a minor inhibition of PIP kinase activity. IP3 concentration decreased in parallel with PI kinase activity. In time sequence studies quercetin in breast carcinoma cells brought down PI kinase and IP3 concentration in 60 min to 5 and 6%, respectively; PIP kinase activity was at 63% of controls. The results demonstrate for the first time in proliferating human breast carcinoma cells a reduction by quercetin of the increased capacity for signal transduction, thus providing a novel and sensitive target in cancer cells.
Insights
Quercetin, a flavonoid, inhibits signal transduction in breast cancer cells by reducing PI kinase activity and inositol 1,4,5-trisphosphate (IP3) levels. This offers a potential new target for cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Signal transduction pathways are often dysregulated in cancer cells, involving enzymes like PI 4-kinase and PI-4-phosphate 5-kinase.
- Elevated activity of these enzymes leads to increased production of the second messenger inositol 1,4,5-trisphosphate (IP3), contributing to cancer cell proliferation.
- Previous studies indicated heightened signal transduction activity in various cancer models, including rat hepatomas and human ovarian and breast carcinomas.
Purpose of the Study:
- To investigate the effect of quercetin, a flavonoid, on signal transduction pathways in human breast carcinoma cells.
- To determine if quercetin can inhibit PI kinase and PIP kinase activities and reduce IP3 concentration.
- To explore quercetin as a potential therapeutic agent targeting signal transduction in cancer.
Main Methods:
- Human breast carcinoma MDA-MB-435 cells were treated with quercetin to assess growth inhibition and cytotoxicity.
- PI kinase and PIP kinase activities were measured in cell extracts and cultured cells exposed to quercetin.
- Inositol 1,4,5-trisphosphate (IP3) concentration was measured in parallel with enzyme activities.
- Time-course studies were conducted to evaluate the rapid effects of quercetin on these molecular targets.
Main Results:
- Quercetin demonstrated significant growth inhibition (IC50 = 55 microM) and cytotoxicity (LC50 = 26 microM) in breast carcinoma cells.
- Quercetin effectively inhibited PI kinase activity in both cell extracts (IC50 = 6 microM) and cultured cells (IC50 = 10 microM).
- A minor inhibition of PIP kinase activity was observed, while IP3 concentration decreased in parallel with PI kinase activity.
- Within 60 minutes, quercetin reduced PI kinase and IP3 levels to 5% and 6% of controls, respectively, with PIP kinase activity at 63%.
Conclusions:
- Quercetin significantly reduces elevated PI kinase activity and IP3 levels in proliferating human breast carcinoma cells.
- This study demonstrates for the first time that quercetin can decrease the heightened signal transduction capacity in these cancer cells.
- The findings suggest that quercetin's inhibition of PI kinase represents a novel and sensitive therapeutic target for breast cancer treatment.