Uroporphyrinogen Decarboxylase Is a Radiosensitizing Target for Head and Neck Cancer

Uroporphyrinogen decarboxylase inhibition sensitizes head and neck cancer to both radiotherapy and chemotherapy.  A Lightning UROD for Head and Neck Cancer They say lightning never strikes the same place twice—unless, of course, that place is a lightning rod. This metal conductor draws damaging bolts to itself and away from sensitive and important structures. Cancer therapies would benefit from similar specificity. The ability to direct radiation and chemotherapy selectively toward cancer cells would decrease treatment side effects and improve patient prognosis. Ito et al. have found that uroporphyrinogen decarboxylase (UROD) can act as a lightning rod for cancer cells, sensitizing them to radiotherapy. Head and neck cancer (HNC) comprises a diverse group of tumors of the upper respiratory and digestive tracts. Alcohol and tobacco use are strongly associated with risk for developing HNC. Using a high-throughput RNA interference screen, the authors identified UROD, an enzyme involved in heme biosynthesis, as a target for enhanced radiosensitization of these tumor types. Knockdown of UROD gene expression with a specific small inhibitory RNA molecule increased cancer cell death both in vitro and in vivo, likely through the production of reactive oxygen species and the resultant rise in oxidative stress. Moreover, elevated amounts of UROD were observed in HNC specimens, and low amounts of cancer-associated UROD correlated with improved patient survival. The sensitizing effects of UROD down-regulation extended to other cancer types and were applicable to both radiation and chemotherapy. These findings suggest that UROD represents a new target for drugs that help cell-killing agents attack tumors and spare normal cells. Head and neck cancer (HNC) is the eighth most common malignancy worldwide, comprising a diverse group of cancers affecting the head and neck region. Despite advances in therapeutic options over the last few decades, treatment toxicities and overall clinical outcomes have remained disappointing, thereby underscoring a need to develop novel therapeutic approaches in HNC treatment. Uroporphyrinogen decarboxylase (UROD), a key regulator of heme biosynthesis, was identified from an RNA interference–based high-throughput screen as a tumor-selective radiosensitizing target for HNC. UROD knockdown plus radiation induced caspase-mediated apoptosis and cell cycle arrest in HNC cells in vitro and suppressed the in vivo tumor-forming capacity of HNC cells, as well as delayed the growth of established tumor xenografts in mice. This radiosensitization appeared to be mediated by alterations in iron homeostasis and increased production of reactive oxygen species, resulting in enhanced tumor oxidative stress. Moreover, UROD was significantly overexpressed in HNC patient biopsies. Lower preradiation UROD mRNA expression correlated with improved disease-free survival, suggesting that UROD could potentially be used to predict radiation response. UROD down-regulation also radiosensitized several different models of human cancer, as well as sensitized tumors to chemotherapeutic agents, including 5-fluorouracil, cisplatin, and paclitaxel. Thus, our study has revealed UROD as a potent tumor-selective sensitizer for both radiation and chemotherapy, with potential relevance to many human malignancies.