Inhibition of DJ-1 induces TFAM secretion from cancer cells to suppress tumor growth via promoting M1 macrophage polarization

DJ-1, also known as PARK7 (Parkinson's disease protein 7), which is involved in cell viability, Apoptosis, transcriptional regulation, and oxidative stress adaptation, is also involved in the pathogenesis of various human diseases including carcinogenesis. Here, we aimed to determine the novel mechanism by which DJ-1 inhibition suppresses tumor growth. Our results showed that DJ-1 knockdown in Cancer cells promoted the secretion of a significantly larger amount of mitochondrial transcription factor A (TFAM) into the Cell Culture medium. DJ-1 knockdown promotes p53 translocation to the mitochondria and stimulates the intrinsic mitochondrial Apoptosis pathway, resulting in TFAM release. Moreover, DJ-1 knockdown induced the downregulation of Sirtuin 3 (SIRT3), which increased the acetylation of TFAM and triggered its release. Furthermore, we found that extracellular TFAM played a critical role in antitumor activity by upregulating the expression of chemokine (CC motif) ligand 4 (CCL4) and chemokine (C-X-C motif) ligand 5 (CXCL5) in Cancer cells, contributing to the promotion of M1 macrophage polarization in the tumor microenvironment (TME). Finally, we confirmed that the DJ-1 inhibitor suppressed tumor growth by increasing TFAM release from Cancer cells and M1 macrophage polarization in vivo. These findings indicate that the depletion of DJ-1 stimulates apoptosis-dependent TFAM secretion that triggers M1 macrophage polarization, indicating a new therapeutic strategy by interfering with the DJ-1 function in Cancer therapy.

Acetylation of TFAM; DJ-1; Extracellular TFAM; M1 macrophage polarization; Tumor growth.