Blocking Phosphodiesterase Activity Inhibits Growth of Lung Cancer Cells

The enzyme phosphodiesterase 4 (PDE4) has been identified as a therapeutic target for cancer therapy, since it is expressed in lung cancer where it interacts with HIF (hypoxia-inducible factor) signaling and promotes progression of the disease.

Hypoxia-inducible factors (HIFs) are transcription factors that respond to changes in available oxygen in the cellular environment, specifically, to decreases in oxygen, or hypoxia. To study the interaction of HIFs and PDE4 - a cyclic nucleotide phosphodiesterase (PDE) known to be involved in various cancer pathologies – investigators at the Max Planck Institute for Heart and Lung Research (Bad Nauheim, Germany) and the Justus Liebig University (Giessen, Germany) worked with cultures of 10 different lung cancer cell lines as well as with human lung cancer xenografts in nude mice.

They exposed the 10 different lung cancer cell lines (adenocarcinoma, squamous, and large cell carcinoma) to hypoxia and assessed expression and activity of PDE4 by real-time PCR, immunocytochemistry, western blotting, and PDE activity assays.

Results published in the April 23, 2012, online edition of the journal Oncogene revealed that expression and activity of distinct PDE4 isoforms (PDE4A and PDE4D) increased in response to hypoxia in eight of the 10 cell lines. Silencing of hypoxia-inducible factor subunits (HIF1alpha and HIF2alpha) by small interfering RNA reduced hypoxic induction of PDE4A and PDE4D and reduced human lung tumor cell proliferation and colony formation. On the other hand, overexpression of PDE4A or PDE4D increased human lung cancer proliferation.

Treatment with a PDE4 inhibitor (PDE4i) blocked tumor xenograft growth in nude mice by attenuating proliferation and angiogenesis. “Our microscopic analysis revealed that the blood vessel growth in the tumors of the mice that had been treated with the inhibitor was significantly reduced,” said senior author Dr. Rajkumar Savai, a researcher at the Max Planck Institute for Heart and Lung Research. “We also observed indicators of decelerated cell division in the tumor cells. Overall, the tumor growth was strongly curbed.”

Coauthor Dr. Werner Seeger, medical director of the Max Planck Institute for Heart and Lung Research, said, “We were able to show that PDE4 plays an important regulation function in cell division in lung tumors and in the development of blood vessels in cancer. Therefore, we hope that we have found a starting point for the development of a treatment here.”

Related Links:
Max Planck Institute for Heart and Lung Research
Justus Liebig University