Knockdown delta-5-desaturase promotes the formation of a novel free radical byproduct from COX-catalyzed ω-6 peroxidation to induce apoptosis and sensitize pancreatic cancer cells to chemotherapy drugs

Abstract

Recent research has demonstrated that colon cancer cell proliferation can be suppressed in the cells that overexpress COX-2 via generating 8-hydroxyoctanoic acid (a free radical byproduct) during dihomo-γ-linolenic acid (DGLA, an ω-6 fatty acid) peroxidation from knocking down cellular delta-5-desaturase (D5D, the key enzyme for converting DGLA to the downstream ω-6, arachidonic acid). Here, this novel research finding is extended to pancreatic cancer growth, as COX-2 is also commonly overexpressed in pancreatic cancer. The pancreatic cancer cell line, BxPC-3 (with high COX-2 expression and mutated p53), was used to assess not only the inhibitory effects of the enhanced formation of 8-hydroxyoctanoic acid from cellular COX-2-catalyzed DGLA peroxidation but also its potential synergistic and/or additive effect on current chemotherapy drugs. This work demonstrated that, by inducing DNA damage through inhibition of histone deacetylase, a threshold level of 8-hydroxyoctanoic acid achieved in DGLA-treated and D5D-knockdown BxPC-3 cells subsequently induce cancer cell apoptosis. Furthermore, it was shown that a combination of D5D knockdown along with DGLA treatment could also significantly sensitize BxPC-3 cells to various chemotherapy drugs, likely via a p53-independent pathway through downregulating of anti-apoptotic proteins (e.g., Bcl-2) and activating pro-apoptotic proteins (e.g., caspase 3, −9). This study reinforces the supposition that using commonly overexpressed COX-2 for molecular targeting, a strategy conceptually distinct from the prevailing COX-2 inhibition strategy used in cancer treatment, is an important as well as viable alternative to inhibit cancer cell growth. Based on the COX-2 metabolic cascade, the outcomes presented here could guide the development of a novel ω-6-based dietary care strategy in combination with chemotherapy for pancreatic cancer.

FADS1 promotes the progression of laryngeal squamous cell carcinoma through activating AKT/mTOR signaling

“…FADS1, as the rate-limiting enzyme of PUFA synthesis, catalyzing DGLA to AA, was reported to be frequently dysregulated in cancers. FADS1 knockdown not only inhibited cancer growth and migration but also enhanced the cytotoxicity of chemotherapy drug [19][20][21]55 .…”

“…Fatty acid desaturase 1 (FADS1) is the key rate-limiting enzyme of the bioactive metabolites which convert dihomo-gamma-linolenic acid (DGLA) to AA 18 . Previous studies have shown that the expression of FADS1 was dysregulated in many cancers and that knockdown of FADS1 not only inhibited cancer growth and migration but also enhanced the cytotoxicity of chemotherapeutic agents [19][20][21][22] . However, the molecular mechanism of FADS1 in laryngeal cancer still remain to be elucidated.…”

Dihomo-γ-linolenic acid inhibits growth of xenograft tumors in mice bearing human pancreatic cancer cells (BxPC-3) transfected with delta-5-desaturase shRNA

“…Western blot was used to assess the expression of Bcl-2, procaspase-9 and procaspase-3, γH2AX and acetyl histone 3 in BxPC-3 and its D5D- KD counterpart upon different treatments in vitro as described elsewhere [34] , [35] , [36] , [37] , [38] . For their expression in vivo, tumor tissues (~ 50–100 mg) were frozen in liquid nitrogen and crushed to a fine powder, then the protein was extracted using CelLytic™ lysis reagent.…”

“…Our lab recently discovered that COX-2-catalyzed DGLA peroxidation can produce the novel anti-cancer byproduct 8-hydroxyoctanoic acid (8-HOA), which can serve as a histone deacetylase inhibitor (HDACi) to inhibit cancer cell growth and metastasis in pancreatic cancer cells, e.g. , BxPC-3 [33] , [34] , [35] , [36] , [37] , [38] . However, the formation of 8-HOA from COX-catalyzed DGLA peroxidation can be limited by delta-5 desaturase (the rate-limiting enzyme to convert DGLA to AA).…”

“…However, the formation of 8-HOA from COX-catalyzed DGLA peroxidation can be limited by delta-5 desaturase (the rate-limiting enzyme to convert DGLA to AA). Thus, we previously used siRNA transfection to knock down D5D in pancreatic cancer cells in vitro to promote formation of 8-HOA from COX-2-catalyzed DGLA peroxidation, which in turn suppressed pancreatic cancer cell growth, migration and invasion [36] , [37] .…”