Source: University of Illinois at Chicago
Summary: Researchers describe new ways to selectively kill prostate cancer cells by exploiting the cells’ revved-up metabolism.
In prostate cancer, the loss of a tumor suppressor gene called PTEN is very common. Without a functional copy of this gene, cancer is much more likely to develop. One of the downstream effects of the loss of PTEN is increased activation of an enzyme called protein kinase B, also known as Akt. Akt has multiple roles in the cell, including driving metabolism and cell proliferation. Hyperactivation of Akt can make cancer cells resistant to chemotherapy, but efforts to develop drugs to suppress Akt in cancer cells have fallen short due to toxicity. The activation of Akt also produces elevated levels of reactive oxygen species or ROS. These are byproducts of metabolism that can cause damage to cellular structures, including DNA. Researchers from the University of Illinois believe that these elevated ROS levels can be exploited to kill cancer cells. The study findings were published in the journal eLife.
To boost ROS levels in cancer cells, the team suppressed ROS scavengers using a natural compound found in cruciferous vegetables, such as broccoli and cauliflower, called phenylethyl isothiocyanate, or PEITC. n a mouse model of PTEN-deficient prostate cancer, PEITC, combined with a drug called rapamycin, almost completely eradicate tumors. Treated mice also showed no recurrence of cancer six months after the treatment stopped. Next, the researchers targeted another downstream metabolic consequence of Akt hyperactivation: an enzyme called hexokinase 2, or HK2. They found that when they deleted the gene for HK2 in the mouse model of prostate cancer, the cancers in those mice stopped growing. The researchers saw similar results in human prostate cancer cells, where the deactivation of HK2 helped restore prostate cancer cell sensitivity to chemotherapy.
Prof. Nissim Hay said, “The increased metabolism of cancer cells presents a sort of Achilles’ heel that we have several ways to exploit in order to very selectively kill these cells while normal cells are left alone.”
More Information: Veronique Nogueira et al, “Selective eradication of cancer displaying hyperactive Akt by exploiting the metabolic consequences of Akt activation”, eLife (2018). DOI: 10.7554/eLife.32213