Alzheimer's and cancer: different sides of the same coin

Lane Simonian

The observation that people with Alzheimer's disease rarely develop cancer and that people with cancer rarely develop Alzheimer's disease suggest that they are opposite diseases: Alzheimer's disease is cell growth without cell death and cancer is cell growth without cell death.  Yet the same apparent triggering factors such as environmental toxins, stress, smoking, etc. appear to be linked to both diseases.

And the same pathway and the same causal oxidating and nitrating agents (hydrogen peroxide and peroxynitrite) also seem linked to both disease.  In Alzheimer's disease, peroxynitrite-mediated nitration inhibits the activation of the phosphatidylinositol 3-kinase-Akt pathway leading to the death of neurons. In cancer, peroxynitrite and hydrogen peroxide-mediated thiol oxidation prevent the deactivation of this pathway leading to uncontrolled cell growth.

It stands to reason that the exact same compounds such as saponins, polysaccharides, and various polyphenols that scavenge hydrogen peroxide and peroxynitrite could positively affect both disease.  In Alzheimer's disease, these compound contribute to the regeneration of neurons, synapses, and axons while limiting the further death of neurons whereas in cancer, these compounds at least in the lab contribute to the death of cancer cells.   

Michael Ellenbogen

I know of at least 3 people who have had both. One was a close friend who died from it. He was lucky as the cancer took him out firtss.

Crushed

Lane Simonian wrote:

Ive said this before I will say it again.  what distinguishes a serious scholar from The "Doctors of Facebook" promoting junk and nonsense are citations to the scientific literature.  

Lane Simonian

When the connection between smoking and lung cancer was first being developed, one scientist said that it was just as likely that wearing panty hose was the cause of lung cancer.  Creating doubt has sometimes served science well, but sometimes it has not served it well at all.

The protein that inhibits the phosphatidylinositol 3-kinase/Akt pathway is called PTEN which is very well known as a tumor surpressor.  The oxidation of PTEN is likely a major factor in cancer and the potential reversal of this oxidation may play a role in the treatment of cancer.  Here is one of many examples:

AIF [Apotosis-Inducing Factor] inhibits tumor metastasis by protecting PTEN from oxidation

In Alzheimer's disease the problem is that the growth pathway (the neuronal survival pathway) is inhibited by nitration:

Phosphatidylinositol 3-kinase is a target for protein tyrosine nitration

The result is the death of neurons:

Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death.

So to simplify, oxidation of PTEN leads to cell growth without cell death and the nitration of the phosphatidylinositol 3-kinase leads to cell death without cell growth.

Crushed

Lane Simonian wrote:

 

So to simplify, oxidation of PTEN leads to cell growth without cell death and the nitration of the phosphatidylinositol 3-kinase leads to cell death without cell growth.

What is the citation that supports this specific conclusion?
 
and by citation  I mean the full CITATION 

June 21, 2019

Rate of Memory Change Before and After Cancer Diagnosis

JAMA Netw Open. 2019;2(6):e196160. doi:10.1001/jamanetworkopen.2019.6160

These novel findings support the possibility of a common pathologic process working in opposite directions in cancer and AD. Identification of a potential association between carcinogenesis and neurodegeneration may open a new avenue in research for prevention and treatment of AD.
 
So a modest statistical association is probably real.  But that is a long way from your claim of definitive or specific causation     

Your misdiscription of the lung cancer   pantyhose example shows the problem  YOu said 

When the connection between smoking and lung cancer was first being developed, one scientist said that it was just as likely that wearing panty hose was the cause of lung cancer.  Creating doubt has sometimes served science well, but sometimes it has not served it well at all.
 

You have drawn exactly the wrong conclusion form this famous incident

   This is well exemplified by the critical and almost derisive comments of Dr. Evarts Graham, a highly respected thoracic surgeon of that time. At a surgical meeting, Dr. Ochsner presented our experience with carcinoma of the lung, and in support of our opinion regarding the causal relation of smoking, presented a slide of a graph demonstrating the progressive increase in cancer of the lung over a 12-year period and a graph demonstrating a parallel increase in the production of tobacco during that same period. In his discussion of Dr. Ochsner's presentation, Dr. Graham stated that we would have obtained the same parallelism by a graph of the production of nylon stockings. He was later converted to the belief that there was a causal relation between tobacco smoking and cancer of the lung, but tragically, his conversion was too late for his own health, since he subsequently died of cancer of the lung.
 Ochsner J. 1999 Jul; 1(3): 106–108.Carcinoma of the Lung and Tobacco Smoking: A Historical Perspective   Michael DeBakey, MD

So no  he did not suggest that "wearing panty hose was the cause of lung cancer"

  but instead that correlation was not causation which is a fundamental tenet of science
 
 Not to mention that he was a distinguished thoracic surgeon with no particular scientific credentials.

Lane Simonian

Good points about Dr. Evarts Graham.  My point was that correlation sometimes turns out to be causation, even though the epidemological studies may seem too limited for some at the time.

The link between oxidation and cancer is not an absolute, but suggestive at this point:

Non-genomic loss of PTEN function in cancer: not in my genes

 

Loss of function of the phosphatase and tensin homolog (PTEN) tumour suppressor contributes to the development of many cancers. However, in contrast to classical models of tumour suppression, partial loss of PTEN function appears to be frequently observed in the clinic. In addition, studies of both humans and mice with reductions in PTEN gene dosage indicate that even partial loss of PTEN function is sufficient to promote some cancer types, particularly in the breast. PTEN expression appears to be tightly controlled both transcriptionally and post-transcriptionally, with several recent studies implicating oncogenic microRNAs in PTEN suppression. The lipid phosphatase activity of PTEN can also be regulated post-translationally via inhibitory phosphorylation, ubiquitination or oxidation. Here we discuss these multiple mechanisms of PTEN regulation. We also put into context recent proposals that changes in this regulation can drive tumour development and address the accompanying evidence for their clinical significance.

Specifically cell growth without cell death:

PTEN Inhibits Cell Proliferation, Promotes Cell Apoptosis, and Induces Cell Cycle Arrest via Downregulating the PI3K/AKT/hTERT Pathway in Lung Adenocarcinoma A549 Cells

 

PTEN plays an essential role in tumorigenesis and both its mutation and inactivation can influence proliferation, apoptosis, and cell cycle progression in tumor cells. However, the precise role of PTEN in lung cancer cells has not been well studied. To address this, we have generated lung adenocarcinoma A549 cells overexpressing wild-type or mutant PTEN as well as A549 cells expressing a siRNA directed toward endogenous PTEN. Overexpression of wild-type PTEN profoundly inhibited cell proliferation, promoted cell apoptosis, caused cell cycle arrest at G1, downregulated p-AKT, and decreased expression of the telomerase protein hTERT. In contrast, in cells expressing a PTEN directed siRNA, the opposite effects on cell proliferation, apoptosis, cell cycle arrest, p-AKT levels, and hTERT protein expression were observed. A549 cells transfected with a PTEN mutant lacking phosphatase activity (PTEN-C124A) or an empty vector (null) did not show any effect. Furthermore, using the PI3K/AKT pathway blocker LY294002, we confirmed that the PI3K/AKT pathway was involved in mediating these effects of PTEN. Taken together, we have demonstrated that PTEN downregulates the PI3K/AKT/hTERT pathway, thereby suppressing the growth of lung adenocarcinoma cells. Our study may provide evidence for a promising therapeutic target for the treatment of lung adenocarcinoma.

On the other hand, the nitration of the phosphatidylinositol 3-kinase in Alzheimer's disease promotes cell death rather than cell growth.

Phosphatidylinositol 3-kinase is a target for protein tyrosine nitration

C B Hellberg 1, S E Boggs, E G Lapetina

Affiliations expand

• PMID: 9826526
 
• DOI: 10.1006/bbrc.1998.9581

 

Abstract

A major mechanism of injury associated with the production of nitric oxide (NO*) in vivo is due to its diffusion-limited reaction with superoxide to form peroxynitrite, which in turn may cause nitration of protein tyrosine residues. To assess the physiological role of tyrosine nitration, it is crucial to identify the proteins that become nitrated. Therefore, we treated lysates from RAW 264.7 cells with 1 mM peroxynitrite and immunoprecipitated tyrosine nitrated proteins. This treatment resulted in the nitration of several proteins, with molecular weights ranging from 60-250 kD. One of these proteins was immunologically identified as the p85 regulatory subunit of the phosphatidylinositol 3-kinase, a key enzyme involved in the signal transduction cascade initiated by many agonists including growth factors. Treatment of RAW 264.7 macrophages with the NO* donor spermine NONOate also induced a nitration of the p85 subunit, demonstrating that this covalent modification also occurs in intact cells. Immunoprecipitation of the p110 catalytic subunit of the phosphatidylinositol 3-kinase co-immunoprecipitated p85 in control lysates. However, p85 could not be detected in the same immunoprecipitates when the lysates had been preincubated with 1 mM peroxynitrite, indicating that the nitration of the p85 subunit may abrogate its interaction with the p110 subunit.

The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal.

1. S G Kennedy, 
2. A J Wagner, 
3. S D Conzen, 
4. J Jordán, 
5. A Bellacosa, 
6. P N Tsichlis, and 
7. N Hay

+Author Affiliations

1. The Ben May Institute for Cancer Research and Department of Pharmacological and Physiological Sciences, The University of Chicago, Illinois 60637, USA.

 

Abstract

 

Serum and certain growth factors have the ability to inhibit programmed cell death (apoptosis) and promote survival. The mechanism by which growth factors deliver an anti-apoptotic signal and the mechanism by which this survival signal is uncoupled from mitogenesis are not clear. We studied five downstream effectors of growth factor receptors--Ras, Raf, Src, phosphoinositide 3-kinase (PI 3-kinase), and Akt (PKB)--for their abilities to block apoptosis. Activated forms of Ras, Raf, and Src, although transforming, were not sufficient to deliver a survival signal upon serum withdrawal. In contrast, inhibition of PI 3-kinase accelerated apoptosis, and an activated form of the serine/threonine kinase Akt, a downstream effector of PI 3-kinase, blocked apoptosis. The ability of Akt to promote survival was dependent on and proportional to its kinase activity. In Rat1a fibroblasts, activated Akt did not alter Bcl-2 or Bcl-X(L) expression but inhibited Ced3/ICE-like activity. Thus, the PI 3-kinase/Akt (PKB) signaling pathway transduces a survival signal that ultimately blocks Ced3/ICE-like activity. These results suggest that uncoupling of survival and mitogenesis can be explained by differing abilities of distinct mitogens to efficiently induce the PI 3-kinase/Akt signaling pathway.

Two distinct signaling pathways regulate peroxynitrite-induced apoptosis in PC12 cells

J J Shacka 1, M A Sahawneh, J D Gonzalez, Y-Z Ye, T L D'Alessandro, A G Estévez

Affiliations expand

• PMID: 16410804
 
• DOI: 10.1038/sj.cdd.4401831

 

Abstract

 

The mechanisms of peroxynitrite-induced apoptosis are not fully understood. We report here that peroxynitrite-induced apoptosis of PC12 cells requires the simultaneous activation of p38 and JNK MAP kinase, which in turn activates the intrinsic apoptotic pathway, as evidenced by Bax translocation to the mitochondria, cytochrome c release to the cytoplasm and activation of caspases, leading to cell death. Peroxynitrite induces inactivation of the Akt pathway. Furthermore, overexpression of constitutively active Akt inhibits both peroxynitrite-induced Bax translocation and cell death. Peroxynitrite-induced death was prevented by overexpression of Bcl-2 and by cyclosporin A, implicating the involvement of the intrinsic apoptotic pathway. Selective inhibition of mixed lineage kinase (MLK), p38 or JNK does not attenuate the decrease in Akt phosphorylation showing that inactivation of the Akt pathway occurs independently of the MLK/MAPK pathway. Together, these results reveal that peroxynitrite-induced activation of the intrinsic apoptotic pathway involves interactions with the MLK/MAPK and Akt signaling pathways.

The same compound--peroxynitrite--can contribute to cancer via oxidation of PTEN (although other oxidants such as hydrogen peroxide can do the same) and to Alzheimer's disease via nitration of the phosphatidylinositol 3-kinase.  It is possible that the strongest of peroxynitrite scavengers can contribute to the treatment of both diseases, in part by partially reversing both processes.

Lane Simonian

I appreciate the push for more evidence, Crushed.  I feel like you are trying to make me do better, where as other people on other sites are just mocking me.