Δ133p53 isoform enhances TLR4 function to promote tumor growth

Abstract

Tumor protein 53 (TP53) acts as a tumor suppressor and is often mutated in cancer. Isoforms of TP53, such as the Δ133p53 family, can promote tumor growth and metastasis. Therefore, targeting Δ133p53 function may represent a new strategy for preventing tumor metastasis. To inform the identification of proteins to target in Δ133p53-expressing tumors, changes at the cell surface were characterized. Inhibition of cell surface trafficking in a mouse model syngrafted with tumors expressing proteins similar to Δ133p53 (Δ122p53) was associated with reduced tumor growth and metastasis. After confirming that changes at the cell surface were important for Δ133p53 tumor promotion, characterization of protein changes at the Δ133p53/Δ122p53 cell surface revealed increased expression of the toll-like receptor 4 (TLR4) and the TLR4 agonist, apoptosis inhibitor 5. Furthermore, inhibition of TLR4 was sufficient to reduce Δ122p53 tumor growth. Altogether, these results suggest a role for Δ133p53 in contributing to tumor progression by stimulating TLR4 function. Furthermore, targeting changes at the cell surface can reduce Δ133p53 tumor promotion.