Tumor cells are often short of oxygen. Carbonaro et al. explain how microtubules (MTs) help control production of a protein that lets the cells survive.
By switching on more than 100 genes, the transcription factor HIF-1 helps cancer cells endure low oxygen levels. HIF-1α, a component of HIF-1, is a promising drug target because more than 70% of tumors overproduce it. How cells control HIF-1α expression remains unclear. The researchers previously discovered that taxol and other drugs that disrupt MT dynamics also reduce production of HIF-1α. The unanswered question was how MTs affect HIF-1α synthesis.
Carbonaro et al. discovered that HIF-1α mRNA attaches to microtubules and scoots along them, presumably traveling to locations where it is translated. When this movement stalled after treatment with taxol or related drugs, cells stowed HIF-1α mRNA inside cytoplasmic structures called P-bodies, where abundant microRNAs shut down translation of HIF-1α mRNA. The researchers found that when they dosed cells with the microtubule-disassembling drug nocodazole and then removed it, the HIF-1α mRNA emerged from hiding, and the cells once again began manufacturing the protein. The researchers also showed that they could thwart taxol's inhibitory effect on HIF-1α by blocking microRNAs and knocking down the P-body protein Argonaute2.
The work indicates that HIF-1α expression depends on the state of the microtubule cytoskeleton. Drugs such as taxol that interfere with microtubule dynamics might kill cancer cells by preventing them from making HIF-1α protein. The findings also raise the possibility that translation of HIF-1α mRNA—and possibly other mRNAs—occurs on MTs.