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Akt inactivation is a key event in indole-3-carbinol-induced apoptosis in PC-3 cells
Sreenivasa R Chinni1, Fazlul H Sarkar
1Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Abstract:
Indole-3-carbinol (I3C) is a bioactive compound present in Brassica vegetables that shows an antitumor activity in experimental animals and inhibits the growth of human cancer cells in vitro. In recent years, studies on prostate cancer (PCa) chemoprevention have been intensified, because there is a long latency for the development of clinical PCa, which makes the PCa a better target for chemoprevention. We have shown previously that I3C induces cell growth inhibition by G(1) cell cycle arrest and induces apoptosis in a dose- and time-dependent manner in PC-3 PCa cells; however, the mechanism(s) by which I3C induces apoptosis in PC-3 cells is still not clear. A cell survival pathway involving phosphatidylinositol 3'-kinase (PI3K) and Akt is known to play an important role in inhibiting apoptosis in response to growth factor signaling, which prompted us to investigate whether this pathway plays any role in I3C-induced apoptosis in PCa cells. Here we report that I3C inhibits the phosphorylation and subsequent activation of Akt kinase. In addition, I3C abrogated epidermal growth factor (EGF)-induced activation of Akt in PC-3 cells. Western blot analyses of EGF receptor showed that I3C down-regulates the EGF receptor levels and its autophosphorylation. This was also accompanied by the inhibition of EGF-induced phosphorylation of PI3K by I3C treatment. Furthermore, the known downstream modulators of the Akt/PI3K cell survival pathway, Bcl-x(L), and BAD proteins showed decreased expression after I3C treatment. From these results, we conclude that I3C-induced apoptosis is partly mediated by the inhibition of Akt activation, resulting in the alterations in the downstream regulatory molecules of Akt activation in PC-3 cells. However, further in-depth investigation is needed to establish a cause-and-effect relationship between Akt pathway and I3C effect.
Insights
Indole-3-carbinol (I3C), found in Brassica vegetables, inhibits prostate cancer cell growth. This study reveals I3C induces apoptosis by blocking the Akt survival pathway, offering potential for cancer chemoprevention.
Area of Science:
- Oncology
- Molecular Biology
- Nutritional Science
Background:
- Indole-3-carbinol (I3C) is a bioactive compound from Brassica vegetables with demonstrated antitumor activity.
- Prostate cancer (PCa) chemoprevention is a growing research area due to the long latency of PCa development.
- Previous studies show I3C induces G1 cell cycle arrest and apoptosis in PC-3 PCa cells, but the mechanism remains unclear.
Purpose of the Study:
- To investigate the role of the phosphatidylinositol 3'-kinase (PI3K)/Akt cell survival pathway in I3C-induced apoptosis in PCa cells.
- To elucidate the molecular mechanisms underlying I3C's apoptotic effects in PC-3 cells.
Main Methods:
- Western blot analysis to assess protein phosphorylation and expression levels.
- Investigation of the effects of I3C on epidermal growth factor (EGF) signaling.
- Evaluation of key downstream modulators of the PI3K/Akt pathway, including Bcl-x(L) and BAD.
Main Results:
- I3C significantly inhibits the phosphorylation and activation of Akt kinase in PC-3 cells.
- I3C abrogates EGF-induced Akt activation and down-regulates EGF receptor levels and autophosphorylation.
- I3C treatment leads to decreased expression of downstream survival proteins Bcl-x(L) and BAD.
Conclusions:
- I3C-induced apoptosis in PC-3 prostate cancer cells is partly mediated by the inhibition of the PI3K/Akt survival pathway.
- I3C affects downstream regulatory molecules of Akt activation, contributing to apoptosis.
- Further research is required to establish a definitive cause-and-effect relationship between the Akt pathway and I3C's anti-cancer effects.