Xiaowei Guo

Cancer cells often exhibit fragmented mitochondria and dysregulated mitochondrial dynamics, but the underlying mechanism remains elusive. Here, we found that the mitochondrial protein death-associated protein 3 (DAP3) is localized to mitochondria and promotes the progression of hepatocellular carcinoma (HCC) by regulating mitochondrial function. DAP3 can promote the proliferation, migration, and invasion of HCC cells in vitro and in vivo by increasing mitochondrial respiration, inducing the epithelial-mesenchymal transition (EMT), and slowing cellular senescence. Mechanistically, DAP3 can increase mitochondrial complex I activity in HCC cells by regulating the translation and expression of MT-ND5. The phosphorylation of DAP3 at Ser185 mediated by AKT is the key event mediating the mitochondrial localization and function of DAP3 in HCC cells. In addition, the DAP3 expression in HCC samples is inversely correlated with patient survival. Our results revealed a mechanism by which DAP3 promotes mitochondrial function and HCC progression by regulating MT-ND5 translation and expression, indicating that DAP3 may be a therapeutic target for HCC.

Macrophages perform key and distinct functions in maintaining tissue homeostasis by finely tuning their activation state. Within the tumor microenvironment, macrophages are reshaped to drive tumor progression. Here we report that tumor necrosis factor α-induced protein 8–like 1 (TIPE1) is highly expressed in macrophages and that depletion of TIPE1 impedes alternative activation of macrophages. TIPE1 enhanced activation of the PI3K/Akt pathway in macrophages by directly binding with and regulating the metabolism of phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3). Accordingly, inhibition of the PI3K/Akt pathway significantly attenuated the effect of TIPE1 on macrophage alternative activation. Tumor-associated macrophages (TAM) in human liver cancer and melanoma tissues showed significantly upregulated TIPE1 expression that negatively correlated with patient survival. In vitro and in vivo, TIPE1 knockdown in macrophages retarded the growth and metastasis of liver cancer and melanoma. Furthermore, blockade or depletion of TGFβ signaling in macrophages abrogated the effects of TIPE1 on tumor cell growth and migration. Together, these results highlight that the phosphoinositide-related signaling pathway is involved in reprogramming TAMs to optimize the microenvironment for cancer progression.Significance:This work provides insight into the fine tuning of macrophage polarization and identifies a potential target for macrophage-based antitumor therapy.

Supplementary Figure from Phosphoinositide-Binding Protein TIPE1 Promotes Alternative Activation of Macrophages and Tumor Progression via PIP3/Akt/TGFβ Axis

Supplementary Figure from Phosphoinositide-Binding Protein TIPE1 Promotes Alternative Activation of Macrophages and Tumor Progression via PIP3/Akt/TGFβ Axis

Supplementary Figure from Phosphoinositide-Binding Protein TIPE1 Promotes Alternative Activation of Macrophages and Tumor Progression via PIP3/Akt/TGFβ Axis

Supplementary Figure from Phosphoinositide-Binding Protein TIPE1 Promotes Alternative Activation of Macrophages and Tumor Progression via PIP3/Akt/TGFβ Axis

Supplementary Figure from Phosphoinositide-Binding Protein TIPE1 Promotes Alternative Activation of Macrophages and Tumor Progression via PIP3/Akt/TGFβ Axis

Supplementary Figure from Phosphoinositide-Binding Protein TIPE1 Promotes Alternative Activation of Macrophages and Tumor Progression via PIP3/Akt/TGFβ Axis

Supplementary Figure from Phosphoinositide-Binding Protein TIPE1 Promotes Alternative Activation of Macrophages and Tumor Progression via PIP3/Akt/TGFβ Axis

Supplementary Data from Phosphoinositide-Binding Protein TIPE1 Promotes Alternative Activation of Macrophages and Tumor Progression via PIP3/Akt/TGFβ Axis