PPFIBP1 activates NF-κB signaling to enhance chemoresistance of multiple myeloma

Easily developed chemoresistance is a major characteristic of multiple myeloma (MM) and the main obstacle in curing MM in the clinic, but the key regulators have not been fully identified. In the current study, we find that PPFIA Binding Protein 1 (PPFIBP1) is highly expressed in the plasma cells from MM patients, and higher PPFIBP1 expression predicts poorer outcomes. PPFPIBP1 enhances chemoresistance of MM cells to the treatment of bortezomib (BTZ), a proteasome inhibitor, and manipulation of PPFPIBP1 can alter chemosensitivity of MM cells to BTZ. Mechanistic studies reveal that PPFPIBP1 directly binds and stabilizes RelA, promotes the cyto-nuclear translocation of RelA, and activates NF-κB signaling pathway. Targeting PPFPIBP1 in a xenograft mouse model of MM prohibits tumor growth and prolongs overall survival of mice. Taken together, our findings suggest that PPFIBP1 is a crucial regulator of chemoresistance to PIs in MM cells, and shed light on developing therapeutic strategies to overcome chemoresistance by targeting PPFIBP1.