Signal transducer and activator of transcription-3 drives the high-fat diet-associated prostate cancer growth

Abstract

Prostate cancer (PCa) is the second leading cause of cancer death in men. PCa progression can be associated with obesity. Signal transducer and activator of transcription-3 (STAT3) plays a crucial role in PCa growth. However, whether STAT3 plays a role in high-fat diet (HFD)-associated PCa growth is unknown. Our data show that HFD feeding increases tumor size, STAT3 phosphorylation, and palmitic acid (PA) level in the xenograft tissues of the PCa-bearing xenograft mouse model. In vitro studies show that PA increases STAT3 expression and phosphorylation (STAT3-Y705) in PCa. Computational modeling suggests strong and stable binding between PA and unphosphorylated STAT3 at R593 and N538. The binding changes STAT3 structure and activity. Functional studies show that both STAT3 mutants (R583A and N538A) and STAT3 dominant negative significantly reduce PA-enhanced STAT3 phosphorylation, PA-increased PCa cell proliferation, migration, and invasion. In the xenograft mouse models, the HFD-increased tumor growth and STAT3 phosphorylation in tumors are reversed by STAT3 inhibition. Our study not only demonstrates the regulatory role of PA/STAT3 axis in HFD-associated PCa growth but also suggests a novel mechanism of how STAT3 is activated by PA. Our data suggest STAT3 as a therapeutic target for the treatment of HFD-associated PCa.

Pentadecanoic Acid, an Odd-Chain Fatty Acid, Suppresses the Stemness of MCF-7/SC Human Breast Cancer Stem-Like Cells through JAK2/STAT3 Signaling

“…Some fatty acids have demonstrated contradictory pre-clinical findings in some in vitro models. For example, palmitic acid (C16:0), an even-chain saturated fatty acid, has been reported to enhance the metastatic potential of melanoma, breast cancer [ 61 ], and prostate cancer cells [ 62 ] in vitro. Furthermore, palmitic acid has been reported to promote colorectal tumorigenesis in vivo [ 63 ].…”

Influence of Diet and Nutrition on Prostate Cancer

“…Previous studies have focused on the relationship between fat-induced inflammation and PCa [29][30][31][32][33]. In a study using prostate-specific phosphatase and tensin homolog (Pten) −/− mice, we found that an HFD doubled the tumor weight in the model mice but did not increase tumor weight in mice administrated celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, or an anti-interleukin (IL)-6 antibody [29].…”

“…Further investigation showed that the mechanism involved local inflammation in the prostate gland induced by the HFD, which led to increased counts of tumor-infiltrating myeloid-derived suppressor cells and production of IL-6 by macrophages, thereby inducing PCa growth by suppression of tumor immunity and via the IL-6/signal transducer and activator of the transcription 3 (STAT3) signaling pathway [29]. A previous study showed that the STAT3 pathway plays an important role in HFD-induced PCa progression in an animal model [30], whereas another study investigating prostate tissue from obese PCa-model mice revealed elevated levels of C-X-C motif chemokine ligand (CXCL)12, C-X-C motif chemokine receptor (CXCR)4, and CXCR7 and showed that a CXCR4 agonist inhibited the migration and invasion of PCa cell lines treated with CXCL12 [31]. Additionally, in vivo and in vitro studies suggest that elevated monocyte chemoattractant protein 1 [also known as chemokine ligand (CCL2)] levels produced by adipocytes and elevated levels of the CCL2 receptor chemokine receptor 2 in prostate tissue are involved in HFD-induced PCa progression [32,33].…”

High-fat diet feeding and palmitic acid increase CRC growth in β2AR-dependent manner

“…Emerging evidence showing palmitic acid serves not only a fatty acid to produce energy, but also an intracellular signaling molecule involved in the development of cancers 9 . Unlike other fatty acids, palmitic acid boosts the metastatic potential of melanoma and breast cancer cells in a CD36-dependent manner 10 ; and also promotes the growth of prostate cancer by activating the signal transducer and activator of transcription 3 11 . However, the specific role of palmitic acid in promoting CRC growth is not known.…”