Intersection of Cancer Pathways Mapped

Researchers have revealed a surprising conspiracy between two molecules known to be hyperactive in many cancers. Even better, the newfound molecular maneuvering may help refine and extend a massive scientific effort to understand and target a key signaling pathway underlying many cancers.

The discovery comes from independent teams that converged on similar results from opposite directions. Headed by researchers at Beth Israel Deaconess Medical Center, both groups first struggled to overcome initial skepticism about the scheming molecular duo they had exposed. With additional experiments and more convincing data, the two groups published their papers together in the April Nature Cell Biology.

The finding “adds an important direct link in the complex regulatory network” between two essential cellular processes that run rampant in many types of cancer, according to an accompanying commentary by researchers at Innsbruck Medical University in Austria, who were not involved in the studies.

“We knew these two switches were on in cancer,” said Pier Paolo Pandolfi, the George C. Reisman professor of medicine at HMS and BID and senior author of one of the studies. “Now we know that one keeps the other one on.”

One of the conspirator molecules (Akt1) hails from the legendary PI3K signaling pathway, an intensively studied central channel that directs normal cell growth and metabolism. The pathway is overstimulated in cancer and other diseases, especially a downstream gang of Akt henchmen in about half of all cancers. An array of first-generation experimental Akt and PI3K inhibitors is advancing through preclinical testing and early clinical trials.

The other lesser-known protein, Skp2, belongs to the intricate molecular network controlling cell division, which also runs amuck in cancer. Skp2 normally teams up with other proteins under the supervision of a strict molecular disciplinarian to help push cells to replicate their DNA and eventually divide. The supervisory tyrant discourages unwanted cell division by routinely sentencing the Skp2 complex to death by proteolysis. In cancerous cells, Skp2 often builds up unfettered, apparently impervious to the usual harsh restraints.

Now it appears the two separate oncogenic processes also work together. By tracing molecular signals that are the equivalent of cell phone calls and text messages from one protein to another, the researchers found that hyperactive Akt1 grabs Skp2 by the tail and plops a signaling molecule (a phosphate) there. With its phosphate enabler, Skp2 can push the cell to divide without limit.

The chain reaction of phosphate signaling passed from protein to protein, culminating with the Akt endowment to Skp2, may start with a mutation of a tumor suppressor gene, such as PTEN, which is implicated in about half of all prostate cancers and nearly as many breast cancers, the researchers said.

The basic dependence of healthy normal cells on the PI3K/Akt signaling pathway motivates scientists to seek more cancer-specific targets. “You risk serious side effects because the key players important in cancer are also important in the normal cell,” said Hui-Kuan Lin, a former postdoc in the Pandolfi lab and first author on the paper from that lab. Lin is now an assistant professor at M.D. Anderson Cancer Center in Houston.

“We need to think of a smarter way to interfere with cell cycle progression,” said Wenyi Wei, HMS assistant professor of pathology at BID and senior author of the other paper. “Most importantly from the clinical point of view, this provides further rationale for developing Akt1 inhibitors and supports further studies of therapeutic approaches to target Skp2.”

In other findings, Lin and his co-authors found that once a phosphate adorned Skp2, the molecule moved from the cell nucleus to the cytoplasm, as seen in human tumors. In experiments, the Skp2 relocation triggered cells to migrate through supporting tissue layers, as they do when cancer metastasizes.

One of the provocative aspects of the research has to do with the strong evidence that Akt binds to the tail of Skp2, Pandolfi said. Several years ago, a crystallography team solved the structure of Skp2 without the tail and showed the bobbed molecule worked perfectly well in its normal cell cycle role. Therefore, they concluded, the tail was superfluous.

The apparent contradiction is, in fact, an agreement, Pandolfi said. Activated Skp2 eludes elimination by the usual ubiquitin (E3) ligase (involving Cdh1) assigned to tag it for destruction in the cellular recycling center, the proteasome, Wei said. Even worse, the activated Skp2 complex is itself a ubiquitin ligase that squelches a downstream tumor suppressor (p27).

The other question that comes up frequently is, What about the mice? Mice do not have the same canonical phosphorylation site for Akt on their Skp2 tails as found in the human cells in the two studies, but a similar site exists on the Skp2 tails of other large mammals, such as rats, dogs, pigs, monkeys and horses. In mice, another more universally conserved mechanism triggers Skp2 activity and its subsequent migration from nucleus to cytosol in the cell, said Wei, who is working through the molecular details with Pandolfi.

Almost three years ago, Wei did not intend to be pursuing this line of research so extensively. He was a new faculty member at BID, just out of his postdoctoral fellowship, when he found himself seated next to the guest of honor at a recruiting dinner for Pandolfi.

When Wei mentioned the Akt–Skp2 connection that he suspected, Pandolfi advised him that his lab had submitted a paper confirming the link. Both scientists knew a young researcher could not afford to be scooped. But soon Pandolfi, newly relocated to BID, found his publication delayed. “We ended up submitting together,” Pandolfi said.

Even better, Pandolfi says, is the prospect of being able to develop combination therapies based on cancer’s molecular signature, such as combining something that targets both Akt activity and short-circuits Skp2’s ability to avoid being degraded in the proteosome.

Students may contact Wenyi Wei at wwei2@bidmc.harvard.edu for more information.

Conflict Disclosure: The authors declare no conflicts of interest.

Funding Sources: Sidney Kimmel Foundation, V foundation, Massachusetts Life Science Center, Emerald Foundation, National Institutes of Health; the content of the work is the responsibility solely of the authors