Credit: Rhoda Baer
Indirectly targeting the prosurvival protein Mcl-1 can reverse chemoresistance in lymphoma and other cancer cells, investigators have reported in The Journal of Biological Chemistry.
The team found that targeting an enzyme known as protein phosphatase 2A (PP2A) inhibited Mcl-1 dephosphorylation, which prompted the loss of Mcl-1 in chemoresistant Burkitt lymphoma cells.
“These findings may lead to a new target for chemoresistant cancer cells,” said Ruth W. Craig, PhD, of Geisel School of Medicine at Dartmouth in Hanover, New Hampshire.
“These cells are resistant to multiple types of standard chemotherapeutic agents because of [Mcl-1] overexpression. However, Mcl-1 expression plummets when we inhibit [PP2A], and then cancer cells subsequently die.”
Dr Craig and her colleagues found that PP2A can be inhibited to stop the removal of phosphate groups from a regulatory motif in Mcl-1 referred to as the PEST region (enriched with amino acids proline, glutamic acid, serine, and threonine).
And inhibiting the removal of phosphate groups, such as at threonine-163 and serine-159, targets the Mcl-1 protein for rapid destruction.
To reach this conclusion, the investigators studied BL41-3 cells, a Burkitt lymphoma cell line that overexpresses Mcl-1 and has proven resistant to multiple treatments.
The team exposed BL41-3 cells to 2 different PP2A inhibitors, okadaic acid and calyculin A. Both drugs prompted an increase in phosphorylation at threonine-163 and serine-159, as well as a decrease in Mcl-1 expression.
Further investigation confirmed that PP2A interacts with Mcl-1. And, as with therapeutic targeting, shRNA knockdown of PP2A/Aα increased phosphorylation while decreasing Mcl-1 expression.
Finally, the investigators showed the increase in Mcl-1 phosphorylation and decrease in its expression occurred well before markers of cell death appeared—about 2 to 3 hours before.
“PP2A is a complex multi-subunit enzyme, and we hope to identify more specifically which form of PP2A is involved in dephosphorylating Mcl-1,” Dr Craig said. “This could [provide us with] a more specific way of causing Mcl-1 destruction.”
