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Page 6 of 12 Israël. J Cancer Metastasis Treat 2019;5:12 I http://dx.doi.org/10.20517/2394-4722.2018.78

of PKC by DAG will then stimulate AMP deaminase that converts AMP into IMP; which decreases AMP
and the stimulation of AMP kinase, cancelling its inhibitory effect on ACC and fatty acid synthesis that
gets activated. Moreover, insulin-mediated PKB effects are opposite to those of PKA that stimulated AMP
kinase. One may then expect that the inhibition of AMP kinase (low AMP and inhibition by PKB) will open
the fatty acid synthesis pathway; the malonyl CoA intermediate increases, closing the fatty acid carnityl
transporter and the beta oxidation source of acetyl CoA. It is thus necessary to open back the glycolytic
source of acetyl CoA that had been closed via DAG PKC stimulation forming the CPI17 inhibitor of PP1,
which blocked PK and PDH. Now that the synthesis of fatty acids and triglycerides is activated by insulin,
DAG will be converted into triglycerides and decrease, suppressing the stimulation of PKC by DAG and
the CPI17 inhibition of PP1, which opens back PK and PDH and the glycolytic source of acetyl CoA (red
pathway Figure 1), while the full anabolic effects of insulin take place. Note that the efflux of citrate from
mitochondria is facilitated by the blockade of isocitrate dehydrogenase by ATP (the ATP/AMP ratio is
elevated). When energy is missing, this ratio decreases, the citrate efflux from mitochondria declines,
closing the citric supply to the fatty acid synthesis route, while the citric Krebs cycle starts turning again; the
acetyl CoA may come again from fatty acid beta oxidation or from glucose, depending on the level DAG, as
indicated in the corresponding black or red boxes.

Well, one of the keys for understanding the rewiring process taking place in cancer is the fact that tumor
cells do maintain the synthesis of fatty acids and triglycerides, which automatically closes the fatty acid
source of acetyl CoA, but tumor cells are unable to open back the glycolytic source of acetyl CoA; as if they
were unable to decrease its DAG blocker, in spite of its conversion into triglycerides. A new supply of DAG
kept PKC and CPI 17 stimulated, inhibiting PP1, then PK and PDH, which closes the glycolytic source of
acetyl CoA. With these two sources of acetyl CoA blocked, the only possible way for tumor cells to get acetyl
CoA and survive, comes from ketone bodies provided by liver cells. It is then essential to find out what
keeps DAG elevated, in spite of its consummation by the active lipid synthesis pathway? Remember that
carcinogenic phorbol-esters act similarly to DAG on PKC; this is discussed in the next section.

A CARCINOGENIC METABOLIC REWIRING PROCESS DESCRIBED IN STEM CELLS AND
DIFFERENTIATED CELLS
We have again represented in Figure 2, the endocrine pancreas but here is a blockade of GABA release,
which might be the consequence of auto-antibodies against GAD that synthesizes GABA; remember that
diabetes Type 1 is provoked by such antibodies that kill beta cells [14,15] . The GABA deficiency may have other
causes, vitamin B6 deficiency (it is the co-factor of GAD) or a GAD mutation as in Stiff person syndrome,
[10]
or result from pesticides and compounds that affect GABA uptake (betel nut addictions) and metabolism .
The most compelling fact in support of the hypothesis is that smoking (a major risk factor for numerous
cancers, including pancreatic) impairs the GABA system. In brain, the increase of glutamate and decrease
of GABA prolongs the activation of the dopaminergic rewarding sensation elicited by nicotine. In the
periphery, the effects of smoking increase the systemic levels of epinephrine and norepinephrine. Whatever
is the cause of the pancreatic GABA deficiency, it leads to an abnormal release of glucagon even when insulin
is released, sending to cells a hybrid catabolic - anabolic message. There is also an effect on beta cells that
become unable to terminate insulin release, a constant leakage of insulin will occur and desensitize insulin
receptors, recalling much aspects of type 2 diabetes or metabolic syndrome. The GABA deficiency should
increase somatostatin release from delta cell, but this is counteracted by an increased epinephrine release
from adrenals due to the GABA deficit; thus, epinephrine strongly inhibits the delta cell and STH release,
increasing the action of GH. It is not the same for alpha cells that are stimulated by epinephrine.

Below the GABA deficient pancreas, three cells are represented: the top one is a stem cell rewiring its
metabolic pathways into a carcinogenic mode after receiving the hybrid hormonal message from the
deficient pancreas, the cell below is a liver differentiated cell, rewiring its metabolism while receiving the
hybrid hormonal message after becoming insulin resistant. The bottom cell is of a muscle fiber also receiving