Re-expression of PPP2R2B in colorectal cancer cells (right column) renders the cells more susceptible to anti-cancer drugs (lower row). Left column shows cancer cells with naturally suppressed PPP2R2B expression.
© 2010 Elsevier
Molecules of phosphate are the primary ‘currency’ for a variety of cellular signaling transactions, and many instructions related to cell division and other essential functions are relayed via targeted phosphorylation of specific proteins by kinase enzymes. Such signals can subsequently be switched off by protein phosphatase 2A (PP2A) enzymes, which trim away phosphate molecules.
Many PP2A enzymes help keep cancer in check, and recent experiments by Qiang Yu at the A*STAR Genome Institute of Singapore and co-workers have revealed a pattern of colon cancer-associated inactivation of PPP2R2B, a gene encoding the PP2A subunit B55β. Following up on these findings, they have now and found1 compelling evidence that B55β contributes to patient response to rapamycin, a promising cancer therapeutic.
Rapamycin targets the mTOR signaling pathway, an important engine of tumor growth, but this drug is not a universally applicable treatment option. “Clinical responses to mTOR inhibitors like rapamycin are generally unpredictable and patient drug resistance can be either intrinsic or acquired,” says Yu.
PP2A enzymes also play an important role in mTOR regulation. The researchers showed that B55β expression specifically inhibits transformation and cancerous growth in cultured colorectal cancer cells. They identified several target proteins that undergo targeted dephosphorylation by B55β-containing PP2A complexes, including the well-known cancer-causing protein c-Myc. The inhibition of c-Myc appears to be a primary mechanism by which B55β constrains cell growth, but it also represents an important link between rapamycin sensitivity and PPP2R2B gene expression.
Rapamycin dramatically inhibited proliferation in cancer cells that produce B55β, but when levels of the protein were reduced, the drug was largely ineffective. The researchers learned that this was because rapamycin treatment stimulates phosphorylation of c-Myc via a previously unidentified pathway, mediated by phosphoinositide-dependent kinase 1 (PDK1). This process can only be kept in check when PPP2R2B is being actively expressed, which allows B55β to directly bind and inhibit PDK1.
According to Yu, the findings suggest a novel cancer signaling pathway that may be important in resistance to rapamycin. Therapeutics targeting PDK1 that could overcome resistance to mTOR inhibitors may be useful for other Myc-driven tumors.
Given the multi-factorial complexity of typical cellular signaling pathways, the researchers are now actively engaged in efforts to uncover other components of the PDK1–Myc cascade. ”We have identified a couple of kinases in this regard, and are now in the process of developing a novel combination strategy for targeting colon cancer based on these findings,” says Yu.
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore.
