p53- and Mevalonate Pathway–Driven Cancers Require Cell-Signaling Protein Arf6 for Metastasis and Drug Resistance
A metabolic pathway that is upregulated in certain breast cancers promotes the disease's progression by activating a cell-signaling protein called Arf6, according to findings published by Hashimoto et al in the Journal of Cell Biology. The study, conducted by a team of researchers at Hokkaido University in Sapporo, Japan, suggests that statin-like drugs may be effective treatments for breast cancer patients whose tumors express high levels of Arf6.
The mevalonate pathway is a metabolic pathway that produces the building blocks for a wide range of biologic molecules, from cholesterol to the long-chain lipid groups that anchor certain proteins to cell membranes. Mutations in the tumor-suppressor protein p53 can upregulate the mevalonate pathway, a phenomenon that enhances the invasiveness of some—but not all—breast cancer cell lines. The Hokkiado research team suspected that the mevalonate pathway might promote invasiveness by activating the Arf6 signaling pathway, which enhances cancer cell invasion and metastasis by promoting the cells' transition to a more motile state.
Study Findings
Researchers found that the mevalonate pathway promotes the recruitment of Arf6 to the plasma membrane, where it can be activated by receptor tyrosine kinases. The pathway does this by generating a lipid group that anchors a protein called Rab11b to cell membranes, allowing Rab11b to deliver Arf6 to its site of activation. Inhibiting Rab11b reduced the invasiveness of a breast cancer cell line, called MDA-MB-231, that expresses high amounts of Arf6 signaling proteins, the researchers discovered.
The Arf6 pathway may also boost the drug resistance of breast cancer cells, and it was found that inhibiting Rab11b, or a component of the Arf6 pathway called EPB41L5, increased the sensitivity of MDA-MB-231 cells to two different cytotoxic compounds.
Statins as Potential Therapy
Statins inhibit the enzyme HMG-CoA reductase, one of the mevalonate pathway's key components. Originally developed to lower cholesterol levels, statins have also been investigated as potential anticancer drugs, but clinical trials have so far produced mixed results.
This study’s data suggest that future efforts might focus on breast cancer patients whose tumors express high levels of Arf6 signaling proteins, and which could therefore be susceptible to drugs that reduce the activity of Rab11b. Indeed, the researchers found that simvastatin increased the drug sensitivity of MDA-MB-231 cells and inhibited the cells' ability to metastasize when injected into mice.
“Blocking the [mevalonate pathway] might effectively kill cancer cells that overexpress the Arf6 pathway, especially in combination with other drugs,” the researchers said.
Developing this therapeutic approach could be crucial, because the researchers found that patients whose tumors expressed high levels of mevalonate pathway components and Arf6 signaling proteins showed poor long-term survival rates.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
