Omega-3 Fatty Acids Prevent Early Pancreatic Carcinogenesis via Repression of the AKT Pathway

Abstract

Pancreatic cancer remains a daunting foe despite a vast number of accumulating molecular analyses regarding the mutation and expression status of a variety of genes. Indeed, most pancreatic cancer cases uniformly present with a mutation in the KRAS allele leading to enhanced RAS activation. Yet our understanding of the many epigenetic/environmental factors contributing to disease incidence and progression is waning. Epidemiologic data suggest that diet may be a key factor in pancreatic cancer development and potentially a means of chemoprevention at earlier stages. While diets high in ω3 fatty acids are typically associated with tumor suppression, diets high in ω6 fatty acids have been linked to increased tumor development. Thus, to better understand the contribution of these polyunsaturated fatty acids to pancreatic carcinogenesis, we modeled early stage disease by targeting mutant KRAS to the exocrine pancreas and administered diets rich in these fatty acids to assess tumor formation and altered cell-signaling pathways. We discovered that, consistent with previous reports, the ω3-enriched diet led to reduced lesion penetrance via repression of proliferation associated with reduced phosphorylated AKT (pAKT), whereas the ω6-enriched diet accelerated tumor formation. These data provide a plausible mechanism underlying previously observed effects of fatty acids and suggest that administration of ω3 fatty acids can reduce the pro-survival, pro-growth functions of pAKT. Indeed, counseling subjects at risk to increase their intake of foods containing higher amounts of ω3 fatty acids could aid in the prevention of pancreatic cancer.

Unconventional diets and nutritional supplements are more common in dogs with cancer compared to healthy dogs: An online global survey of 345 dog owners

“…5 The body of literature surrounding effects of fatty acids on cancers is larger than that of CBD oil. Many in vitro studies have been conducted and provide evidence that fatty acids such as docosahexaenoic acid and eicosapentaenoic acid are effective in reducing cancer cell viability through a variety of mechanisms in human cell lines [19][20][21][22][23] ; however, only one in vitro study has been conducted in canine cell lines. 24 One in vivo study investigated supplementation of menhaden oil in dogs with nasal carcinoma and found it may alleviate inflammatory side effects of radiation therapy 25 while another found n-3 PUFA supplementation increased disease-free interval and survival time in dogs with lymphoma; however, arginine was also supplemented in this T A B L E 5 Time spent researching pet health topics, pet nutrition and nutritional supplements, proportion of pet owners feeding nutritional supplements and number of supplements fed per dog in dogs with cancer and healthy dogs from an online dog owner survey regarding diet and supplement use Note: N, number of respondents; %, proportion; IQR, inter-quartile range reported as the range from Q1 to Q3; min, minimum; max, maximum.…”

Metabolism of pancreatic cancer: paving the way to better anticancer strategies

“…Polyunsaturated fatty acids, mainly containing the ω3 and ω6 families, dually affect pancreatic cancer. ω3 fatty acids inhibit cancer cell proliferation via reducing AKT phosphorylation, but ω6 fatty acids increase AKT phosphorylation [85]. However, a transcriptomics and metabolomics study revealed that lipase and a panel of fatty acids are significantly decreased in pancreatic tumors, and two saturated fatty acids, palmitate, and stearate, showed an obvious ability to inhibit the proliferation of pancreatic cancer cells [86].…”

p110γ deficiency protects against pancreatic carcinogenesis yet predisposes to diet-induced hepatotoxicity

“…The P.J.G. laboratory has previously described the impact of a high-fat diet (HFD) enriched in polyunsaturated fatty acids on the progression of pancreatic neoplasia (31)(32)(33)(34). Given the connection between obesity and PI3K, this study includes cohorts of mice on an HFD enriched with ω-6 fatty acids.…”

“…As the HFD appears to establish a tumor permissive phenotype and activate AKT signaling independent of p110γ, we next evaluated the effects of in vitro p110γ inhibition when combined with administration of the main component of the in vivo HFD: ω-6 polyunsaturated fatty acids, in this case, linoleic acid (LA). We again used Panc-1, MiaPaca-2, and AsPC-1 PDAC cell lines and administered 40 μM of LA, the working concentration as previously determined empirically in our laboratory (34). In response to LA, each cell line displayed increased expression of p110α, p110β, and p110γ both at the mRNA (Fig.…”