In work predating the Michelakis paper, Barbara Heerdt, Michele Houston and Leonard Augenliccht of the Albert Einstein Cancer Center showed that, among other things, ."the development of cancer in the colonic mucosa includes alterations in mitochondrial enzymatic activity and elevations in the mitochondrial membrane potential (MMP). They showed "that the intrinsic MMP has a significant influence on steady state mitochondrial activity and the extent to which cells enter butyrate-mediated growth arrest and apoptotic cascades. Here, we report that the MMP is also profoundly linked to important tumorigenic properties of the cells. Compared with cells with lower MMP, cells with elevated intrinsic MMP have an enhanced capacity to
(a) respond to hypoxia by avoiding apoptosis and initiating angiogenesis,
(b) escape anoikis and grow under anchorage-independent conditions, and
(c) invade the basement membrane.
Combined with our previous work, these data implicate the intrinsic MMP of colonic carcinoma cells in determining the probability of tumor expansion and progression. " Growth Properties of Colonic Tumor Cells Are a Function of the Intrinsic Mitochondrial Membrane Potential

Fish oil works synergistically with butyrate to cause apoptosis in colon cells.Fish oil increases mitochondrial phospholipid unsaturation

"These data indicate that DHA and butyrate potentiate mitochondrial lipid oxidation and the dissipation of mitochondrial membrane potential which contribute to the induction of apoptosis."
The role of docosahexaenoic acid in mediating mitochondrial membrane lipid oxidation and apoptosis in colonocytes (pdf) .

"Collectively, these data show that the combination of DHA and butyrate, compared with butyrate alone, further enhances apoptosis by additionally recruiting a Ca2+-mediated intrinsic mitochondrial pathway" Docosahexaenoic Acid and Butyrate Synergistically Induce Colonocyte Apoptosis by Enhancing Mitochondrial Ca2+ Accumulation html

"DHA is incorporated into mitochondrial membrane phospholipids, thereby enhancing oxidative stress induced by butyrate metabolism" and "These data indicate that DHA and butyrate potentiate mitochondrial lipid oxidation and the dissipation of MP which contribute to the induction of apoptosis." The role of docosahexaenoic acid in mediating mitochondrial membrane lipid oxidation and apoptosis in colonocytes

"EPA and DHA induced apoptosis, as indicated by a loss of mitochondrial membrane potential, increased caspase activity and increased DNA fragmentation " Mechanisms of omega-3 fatty acid-induced growth inhibition in MDA-MB-231 human breast cancer cells

Fish oils are incorporated into mitochondrial membranes: " There was significantly greater incorporation of the n-3 polyunsaturated fatty acids DHA and EPA into the cardiolipin of the mitochondrial membrane in animals that consumed fish oil compared to corn oil. There was also a corresponding reduction in n-6 fatty acids (20:2 and 20:3) in the cardiolipin of fish oil fed rats compared to corn oil fed rats." Effects Of Fish Oil And Butyrate On Diet-mediated Apoptosis At The Promotion Stage Of Colon Carcinogenesis

"Figure 6. Proposed molecular model of DHA and butyrate-induced apoptosis. Butyrate induces colonocyte apoptosis via a nonmitochondrial, Fas-mediated, extrinsic pathway. DHA and butyrate, in combination, synergistically perturb intracellular Ca2+, stimulating mitochondrial Ca2+ uptake. This directly or indirectly decreases cytosolic Ca2+ and promotes SOC-mediated entry via plasma membrane channels. Mitochondrial Ca2+ accumulation subsequently triggers the opening of the permeability transition pore (PTP) and release of proapoptotic molecules like cytochrome c and other factors such as apoptosis-inducing factor (AIF), and second mitochondrial activator of caspases (smac/DIABLO). Together, these effects culminate in the induction of procaspases and downstreamcaspases that execute cellular apoptosis." The Michelakis paper calls the PTP the MTP, or "mitochondrial transition pore"

Researchers at Texas A&M had previously shown that butyrate induces apoptosis through a Fas-mediated, non-mitochondrial pathway. This study demonstrates that the incorporation of DHA into the lipid layer of a cancer cell facilitates calcium ion uptake and apoptosis.

"In an extension of our findings, we show for the first time that the combination of DHA and butyrate, compared with butyrate alone, further enhances apoptosis by additionally recruiting a Ca2+-dependent mitochondrial-intrinsic pathway. Notably, DHA-enriched mitochondria were sensitized to rapidly sequester Ca2+, which served to trigger apoptosis in the presence of butyrate."

Note the lipid must be long chain, unsaturated fatty acids..

DCA and tributyrin/DHA act almost identically
in activating apoptosis

DCA also decreases cytosolic calcium ions: "As predicted, DCA-treated A549 cells have lower [Ca2+]i compared to untreated cells (Figure 5A). The decrease in [Ca2+]i occurs within 5 min and is sustained after 48 hr of DCA exposure" . From Michelakis paper, page 43.

The Michelakis paper also states:, "DCA-induced apoptosis proceeds by two pathways, one in the mitochondria, where depolarization activates mitochondria-dependent apoptosis, and the other at the plasmalemmal level, where activation/upregulation of Kv1.5 channels decreases [K+]i, activating caspases." Plasmalemmal level means cell membrane level. If you examine the image above from the Kolar paper, you will see that butyrate and DHA initiates apoptosis via the same mechanisms as DCA.

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