IISc researchers have uncovered a novel mechanism by which cancer cells in circulation stay alive. They found the protein kinase AMPK gets activated when cancer cells detach from extracellular matrix, and, in turn, inhibits another protein kinase Akt. This finding overturns the two-decade dogma that Akt is vital for the survival of circulating cancer cells. The researchers have also found two drug targets to prevent metastasis.
Researchers at Bengaluru’s Indian Institute of Science (IISc) have uncovered a novel molecular mechanism by which cancer cells survive during the time they are in circulation after detaching from the primary cancer site and before they could attach to the extracellular matrix at a different site and restart cell division, thus causing cancer metastasis. In the process, the team led by Prof. Annapoorni Rangarajan from the Department of Molecular Reproduction, Development and Genetics has identified two potential drug targets to prevent metastasis. The results were published in the journal Cancer Research.
Prof. Rangarajan’s team had a decade ago found that a particular protein called the AMP-activated protein kinase (AMPK) gets activated when cancer cells detach from the extracellular matrix. Now, the team got headlong into researching its connection with another protein kinase called Akt (protein kinase B) as other researchers had all along highlighted how critical Akt was for cancer cells to survive.
It was always thought that the AMPK protein suppresses tumour growth while Akt behaves as a promoter. “But what we saw in our study was a complete reverse, which was a surprise. We found AMPK getting activated in circulating cancer cells and, in turn, suppressing the Akt activity,” says Prof. Rangarajan. “The AMPK-mediated Akt inhibition is necessary for cancer cells to survive during circulation.” The AMPK that gets activated in circulating cancer cells keeps them alive at the cost of cell division.
Once the circulating cancer cells reattach to the extracellular matrix at a distant site from the primary tumour, Akt gets reactivated and AMPK gets inhibited. The protein Akt is required for cell growth and proliferation while AMPK is needed for growth suppression.
“Our study based on breast cancer cells has refuted the 20-year-old dogma that Akt is vital for the survival of circulating cancer cells,” she says proudly. “We have established that there is a role-reversal of Akt and AMPK proteins in breast cancer progression.”
No link between Akt and AMPK proteins in cancer metastasis was known till now. The results of the latest study, therefore, become all the more important.
The AMPK-mediated inhibition of Akt is through increased levels of a phosphatase (PHLPP2) that removes the phosphate group from Akt. “The PHLPP2 was also believed to suppress tumour. But in circulating cancer cells, PHLPP2 also becomes a tumour promoter,” Prof. Rangarajan says. “So molecules that inhibit AMPK and PHLPP2 can be developed as effective anti-metastasis agents,” she says.
“We used mouse models to support our findings from cancer cell lines. Since there are no chemicals available to inhibit PHLPP2, we used a RNA interference strategy to reduce PHLPP2 levels. This resulted in impairment of the metastatic potential of cancer cells,” says Dr. Manipa Saha from the Department of Molecular Reproduction, Development and Genetics and first author of the paper.
“Our work focuses mainly on breast cancer cells as the first observation of AMPK-Akt crosstalk was made in these cells in our laboratory. However, our results on mechanistic details of the inverse crosstalk are expected to hold true in other cancer cells. But more research is needed to confirm this,” says Saurav Kumar, a coauthor of the paper.
The diabetic drug metformin has been repurposed as an anticancer agent. “Since metformin activates AMPK, treatment using this drug may actually promote metastasis. So metformin should not be used for cancer treatment without fully understanding its side effects,” Prof. Rangarajan warns.