Apigenin Increases SHIP-1 Expression, Promotes Tumoricidal Macrophages and Anti-Tumor Immune Responses in Murine Pancreatic Cancer

Abstract

Pancreatic cancer (PC) has an extremely poor prognosis due to the expansion of immunosuppressive myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) in the inflammatory tumor microenvironment (TME), which halts the recruitment of effector immune cells and renders immunotherapy ineffective. Thus, the identification of new molecular targets that can modulate the immunosuppressive TME is warranted for PC intervention. Src Homology-2 (SH2) domain-containing Inositol 5′-Phosphatase-1 (SHIP-1) is a lipid signaling protein and a regulator of myeloid cell development and function. Herein, we used the bioflavonoid apigenin (API) to reduce inflammation in different PC models. Wild type mice harboring heterotopic or orthotopic PC were treated with API, which induced SHIP-1 expression, reduced inflammatory tumor-derived factors (TDF), increased the proportion of tumoricidal macrophages and enhanced anti-tumor immune responses, resulting in a reduction in tumor burden compared to vehicle-treated PC mice. In contrast, SHIP-1-deficient mice exhibited an increased tumor burden and displayed augmented proportions of pro-tumor macrophages. These results provide further support for the importance of SHIP-1 expression in promoting pro-tumor macrophage development in the pancreatic TME. Our findings suggest that agents augmenting SHIP-1 expression may provide novel therapeutic options for the treatment of PC.

Marine Seagrass Extract of Thalassia testudinum Suppresses Colorectal Tumor Growth, Motility and Angiogenesis by Autophagic Stress and Immunogenic Cell Death Pathways

“…Although cancer cells can escape immune-surveillance by tuning down autophagy, phytochemical agents with immunogenic and autophagy-promoting properties may enhance antitumor immunity by inducing autophagic cell death [ 54 ]. For apigenin, luteolin, and chrysoeriol, immunogenic and autophagy-promoting properties have already been reported ( Supplementary Table S6 ) [ 32 , 33 , 38 , 39 , 59 ]. In addition, we previously found that treatment with another purified TTE constituent (Thalassiolin B) fully mimicked ROS production and tumor regression by polyphenolic fraction treatment in a xenograft colorectal cancer model [ 16 ].…”

Targeting Akt in cancer for precision therapy

“…While PDK1, mTOR, TBK1 and MERTK are Akt-phosphorylating kinases, the lipid phosphatases such as phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Src homology 2 domain-containing inositol-5-phosphatase (SHIP) can inhibit the phosphorylation of Akt by PI3K pathway [ 112 – 114 ]. Mechanistically, PTEN and SHIP convert PIP3 into PI(4,5)P2 and PI(3,4)P2, respectively.…”

Targeting SHIP1 and SHIP2 in Cancer

“…Further studies on the pelorol agonists ZPR-151 16 and AQX-435 17 would seem to be a logical starting point for this area. Pre-clinical studies clearly indicate a link between SHIP modulation and the growth and development of many cancers [ 185 , 186 ]. Armed with the structural information provided by x-ray crystallographers, medicinal chemistry studies can now be fully engaged to develop paralog selective potent inhibitors and agonists which can then be evaluated in tumor models.…”