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Open AccessArticle

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

1
Department of Molecular Medicine, Morsani College of Medicine at the University of South Florida, Tampa, FL 33612, USA
2
Comparative Medicine at the University of South Florida, Tampa, FL 33612, USA
3
The Terry Fox Laboratory, BC Cancer, Vancouver, BC V5Z 1L3, Canada
4
Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne 3004, Australia
5
Anatomic Pathology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
6
Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(12), 3631; https://doi.org/10.3390/cancers12123631
Received: 23 November 2020 / Accepted: 2 December 2020 / Published: 4 December 2020
(This article belongs to the Section Cancer Immunology and Immunotherapy)
Src Homology 2 (SH2) domain-containing Inositol 5’-Phosphatase-1 (SHIP-1) is an essential protein and the master regulator of myeloid cell development and function that impacts tumor immunity. We previously published that SHIP-1 regulates the expansion and function of immunosuppressive myeloid cells, which correlated with pancreatic cancer progression in mice. Here, we show that the bioflavonoid Apigenin restored SHIP-1 expression, significantly increased tumoricidal Tumor-Associated Macrophages (TAM) while significantly decreased immunosuppressive TAM percentages and improved anti-tumor immune responses in the tumor microenvironment using different pancreatic cancer models. Our research findings suggest that SHIP-1 may be a potential novel therapeutic target to promote the development of tumoricidal TAM that can assist in the treatment of pancreatic cancer.
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. View Full-Text
Keywords: SHIP-1; pancreatic cancer; apigenin; myeloid homeostasis; tumor immunity SHIP-1; pancreatic cancer; apigenin; myeloid homeostasis; tumor immunity
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MDPI and ACS Style

Villalobos-Ayala, K.; Ortiz Rivera, I.; Alvarez, C.; Husain, K.; DeLoach, D.; Krystal, G.; Hibbs, M.L.; Jiang, K.; Ghansah, T. Apigenin Increases SHIP-1 Expression, Promotes Tumoricidal Macrophages and Anti-Tumor Immune Responses in Murine Pancreatic Cancer. Cancers 2020, 12, 3631. https://doi.org/10.3390/cancers12123631

AMA Style

Villalobos-Ayala K, Ortiz Rivera I, Alvarez C, Husain K, DeLoach D, Krystal G, Hibbs ML, Jiang K, Ghansah T. Apigenin Increases SHIP-1 Expression, Promotes Tumoricidal Macrophages and Anti-Tumor Immune Responses in Murine Pancreatic Cancer. Cancers. 2020; 12(12):3631. https://doi.org/10.3390/cancers12123631

Chicago/Turabian Style

Villalobos-Ayala, Krystal; Ortiz Rivera, Ivannie; Alvarez, Ciara; Husain, Kazim; DeLoach, DeVon; Krystal, Gerald; Hibbs, Margaret L.; Jiang, Kun; Ghansah, Tomar. 2020. "Apigenin Increases SHIP-1 Expression, Promotes Tumoricidal Macrophages and Anti-Tumor Immune Responses in Murine Pancreatic Cancer" Cancers 12, no. 12: 3631. https://doi.org/10.3390/cancers12123631

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