A recent study shows that the transport receptor Importin-11 relocates PTEN, a tumor suppressor, to the nucleus, preventing its degradation in the cytoplasm. Mice lacking Importin-11 are prone to lung cancers, and its absence in human prostate and lung tumors signals a poorer prognosis.
Levels of PTEN, a key tumor suppressor, often plummet in cancer cells. A recent study suggests that the transport receptor Importin-11 (IPO11) helps maintain PTEN levels by shuttling the protein into the nucleus, where it's protected from degradation and may continue to control cell proliferation and survival.
PTEN mutations frequently occur in cancers. Even in tumors that lack these alterations, the protein is often scarce or absent, indicating that other mechanisms that control PTEN levels may be defective. At first, researchers suspected that mutant enzymes that ubiquitinate PTEN, thus spurring its destruction by the proteasome, were overactive, but the genes that encode these proteins are rarely mutated in patients with cancer. Another possible mechanism is that the transportation machinery that moves some of the cell's PTEN supply into the nucleus is faulty, allowing more of the protein to be destroyed in the cytoplasm.
To test this hypothesis, Lloyd Trotman, PhD, of Cold Spring Harbor Laboratory in New York, and colleagues focused on one transport receptor, IPO11, which latches onto ubiquitinated molecules and helps ferry them into the nucleus. Experimenting on prostate cancer cells, they showed that mutant IPO11 impaired PTEN transport, accelerating its breakdown in the cytoplasm. Thus IPO11 protects PTEN by helping it to take refuge in the nucleus.
However, IPO11 provides protection in another way, the researchers found. The transport receptor also shuttles UBE2E1, an enzyme necessary for PTEN ubiquitination, into the nucleus. Thanks to IPO11, normal cells keep all of their UBE2E1 in the nucleus, allowing PTEN to continue functioning in the cytoplasm. In cells lacking IPO11, UBE2E1 remains in the cytoplasm and promotes the destruction of PTEN.
To gauge the effects of IPO11 in vivo, the researchers studied mice engineered to have reduced levels of the protein in most of their tissues. The only organs in which tumors consistently grew in the animals were the lungs. Before they were 30 months old, all of the rodents had developed the tumors, whereas control mice remained cancer-free.
Because PTEN levels often decline in prostate tumors, the researchers also wanted to measure the effects of reduced IPO11 in the prostate. The mice they had engineered had normal prostate levels of the protein, however. To overcome this obstacle, the scientists used CRISPR/Cas9 to eliminate IPO11 specifically from the prostate in a different group of mice. After 8 weeks, the rodents had developed precancerous prostatic neoplasias, whereas the tissues of control mice remained normal.
Trotman and colleagues then analyzed human cancer samples. Because of the high incidence of lung tumors in the engineered rodents, they tested human lung tumors and found that those with little or no PTEN usually had little or no IPO11. These tumors typically were more advanced and more likely to have metastasized. The team saw a similar picture for prostate tumors. When IPO11 was missing, the tumors were more likely to have metastasized, and patients' odds of relapse after a prostatectomy were higher.
IPO11′s role was surprising because “it is supposed to have housekeeping functions,” says Trotman, but the study shows that it's part of “an inherent safety system to make sure degradation of PTEN doesn't happen by default.” Trotman adds that testing for IPO11 deletions could provide a more accurate prognosis for patients with prostate cancer.
“This study adds a new insight into the mechanism by which PTEN can be downregulated,” says Andrea Alimonti, MD, of the Institute of Oncology Research in Switzerland, who wasn't connected to the research.
Nicholas Leslie, PhD, of Heriot-Watt University in the UK, agrees that the work is important because it suggests that “the importins can represent tumor-suppressing genes.” He cautions, however, that IPO11 carries several cargoes, and changes in the levels of these molecules, not PTEN, could be responsible for the tumors in the engineered mice. –Mitch Leslie