Pyruvate dehydrogenase kinase 1 and carbonic anhydrase ix targeting in hypoxic tumors

Abstract

Pyruvate dehydrogenase kinase 1 (PDHK1) and carbonic anhydrase IX (CAIX) are some of the most hypoxia-inducible proteins associated with tumors, implicated in glucose metabolism and pH regulation, respectively. They both appear to be necessary for model tumor growth, and their high level of expression in human tumors predicts poor patient outcome. Another thing they have in common is that hypoxia not only induces their expression but also their enzymatic activity. This work therefore simultaneously targets these two hypoxia-inducible proteins either pharmacologically or genetically in vitro and in vivo, leading to decreased cancer cell survival and significantly slower model tumor growth. It also suggests that CAIX and PDHK1 are important for cells originating from a colorectal primary tumor, as well as from its metastasis. Moreover, our analysis reveals a unique relationship between these two HIF-1 target genes. In conclusion, the attributes of PDHK1 and CAIX predict them to be promising targets for the design of new, specific inhibitors that could negatively influence tumor cell proliferation and survival, or increase efficacy of standard treatment regimens, and at the same time avoid normal tissue toxicity.