Dietary palmitate cooperates with Src kinase to promote prostate tumor progression

Abstract

Numerous genetic alterations have been identified during prostate cancer progression. The influence of environmental factors, particularly the diet, on the acceleration of tumor progression is largely unknown. Expression levels and/or activity of Src kinase are highly elevated in numerous cancers including advanced stages of prostate cancer. In this study, we demonstrate that high-fat diets (HFDs) promoted pathological transformation mediated by the synergy of Src and androgen receptor in vivo. Additionally, a diet high in saturated fat significantly enhanced proliferation of Src-mediated xenograft tumors in comparison with a diet high in unsaturated fat. The saturated fatty acid palmitate, a major constituent in a HFD, significantly upregulated the biosynthesis of palmitoyl-CoA in cancer cells in vitro and in xenograft tumors in vivo. The exogenous palmitate enhanced Src-dependent mitochondrial β-oxidation. Additionally, it elevated the amount of C16-ceramide and total saturated ceramides, increased the level of Src kinase localized in the cell membrane, and Src-mediated downstream signaling, such as the activation of mitogen-activated protein kinase and focal adhesion kinase. Our results uncover how the metabolism of dietary palmitate cooperates with elevated Src kinase in the acceleration of prostate tumor progression. K E Y W O R D S palmitate/fatty acid metabolism/Src kinase/prostate cancer 1 | INTRODUCTION Prostate cancer is the most common cancer in men and one of the leading causes of cancer-related deaths in developed countries. 1 Diet is considered a critical environmental risk factor in prostate cancer progression. 2 Numerous epidemiological studies indicate that obesity, higher body mass index, or adult weight gain significantly increases the risk of aggressive prostate cancer, mortality, and recurrence of prostate cancer. 3-8 A high-fat diet (HFD) or certain dietary saturated fatty acids (FAs) including palmitic acid (PA) and myristic acid (MA) are associated with advanced stages of prostate cancer and increase the risk of prostate cancer-specific mortality. 3,5,7,9 Incorporation of excess free FAs into cancer cell membranes promotes cancer invasion by reduction of cell-cell contact and increase of surface adhesion. 10 However, the interaction of dietary factors with oncogenic events to regulate tumor progression is not well-understood. Numerous genetic alterations including aberrant expression and/ or loss of tumor suppressor genes have been identified in the initiation and progression of prostate tumors. 11 Among those oncogenic events, overexpression and/or activation of Src kinase is common in advanced stages of prostate cancer. 12,13 Src kinase is a pleiotropic activator to mediate numerous signal transduction pathways initiated by G-protein coupled receptors, β1-integrin, growth factor receptors, and others. 14,15 The activation of Src kinase promotes cell survival, proliferation, migration, and invasion in The Prostate. 2019;79:896-908. wileyonlinelibrary.com/journal/pros

Dietary palmitic acid promotes tumor growth and epithelial-mesenchymal transformation in prostate cancer

“…Our study focused on the effect of PA, one of the main components of lipids, on PCA development. Earlier articles indicated that PA could increase invasiveness of cancer cells [17,36,37]. Our research showed that PA induced tumor growth in a PCA xenotransplantation model and accelerated PCA progression in c-Myc T mice.…”

Fatty-Acid Uptake in Prostate Cancer Cells Using Dynamic Microfluidic Raman Technology

“…However, it was not conclusive that the inhibition was due to metabolic competition or competitive uptake. With PA, also a FA that induces metastatic effects of PC-3 cells [42,43], it is hypothesised that the uptake could be inhibited by omega-3 FAs such as DHA and EPA. The Raman results acquired here suggest that the omega-3 FAs do inhibit the uptake of PA by the PC-3 cells.…”

Dietary Fat and Cancer—Which Is Good, Which Is Bad, and the Body of Evidence

“…However, further analysis revealed that tumour incidence (involving several tumour sites in mice) was positively associated with total caloric intake, regardless of the level of dietary fat [95]. In addition, in isocaloric diets, it is the fat type that matters in tumour promotion, and progression [96][97][98], as the impact of different FAs on signalling pathways involved in cell proliferation varies [99,100]. Furthermore, interpolating animal data is tricky, in part because of differences in metabolism, in part due to factors which, unlike in vivo studies, cannot be controlled in full in human studies (e.g., total caloric intake, macronutrient, and micronutrient composition, lifestyle factors, etc.…”

“…A diet high in PA enhanced the proliferation of prostate cancer xenografts in comparison with a diet high in unsaturated fat. PA increased the level of Src kinase and Src-mediated downstream signalling, including MAPK activation, and also enhanced Src-dependent mitochondrial β-oxidation [98]. PA increased the invasiveness of AsPC-1 pancreatic cancer cells via the TLR-4/ROS/NF-κB/matrix metalloproteinase-9 (MMP-9) signalling pathway [148] and promoted metastasis in several human oral carcinoma cell lines expressing high levels of cluster of differentiation 36 (CD36) [149].…”