Olfactory Receptors as Tumor Suppressors in Cutaneous T-Cell Lymphoma via p38γ Pathway Modulation

• Two compounds targeting p38γ LBS enhance olfactory transduction with unique combinations of ORs.

• OR4N5 is identified as an exemplar tumor suppressor in CTCL, possibly modulating TCR activation through interaction with CD3E.

Our previous observations revealed p38γ's significant overexpression in cutaneous T cell lymphoma (CTCL), small molecule inhibitors of the lipid binding site of p38γ, CSH18 and CSH71 exhibited strong cytotoxicity against CTCL cells while sparing healthy cells. We report here that both compounds significantly enhanced the activity of the Olfactory Transduction pathway, and each induces a unique combination of olfactory receptors. CSH71 increased gene expression of OR4N5, an olfactory receptor that functions as a tumor suppressor in cutaneous T cell lymphoma Hut78 cells; its suppression is associated with accelerated cell proliferation. The study elucidates the potential mechanism wherein the targeting of the p38γ lipid-binding site affects the alternative p38 phosphorylation via ZAP70 thereby TCR activation. The expression of OR4N5 and CD3E is reduced in CTCL; scattered aberrant CD3Es are in the cytosol and surrounds the nuclear envelope. Membranous OR4N5 no longer interacts with CD3E in CTCL cells, which sets TCR signaling transduction on loose via depending on other mechanisms such as the DLGH1-p38γ-NFAT axis. Analysis of public datasets shows that most olfactory receptors are significantly downregulated in cancer, suggesting their grassroot tumor suppressors role when network emerged as they teamed together against cancer.