Mini Review: Opposing Pathologies in Cancer and Alzheimer's Disease: Does the PI3K/Akt Pathway Provide Clues?

Abstract

This minireview is a brief overview examining the roles of insulin-like growth factors (IGFs) and the PI3K/Akt pathway in two apparently unconnected diseases: Alzheimer's dementia and cancer. For both, increased age is a major risk factor, and, in accord with the global rise in average life expectancy, their prevalence is also increasing. Cancer, however, involves excessive cell proliferation and metastasis, whereas Alzheimer's disease (AD) involves cell death and tissue destruction. The apparent "inverse" nature of these disease states is examined here, but also some important commonalities in terms of the PI3K/Akt pathway, glucose utilization and cell deregulation/death. The focus here is on four key molecules associated with this pathway; notably, the insulin receptor substrate 1 (IRS-1), cellular tumor antigen p53 (p53), peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) and low-density lipoprotein receptor-related protein-1 (LRP1), all previously identified as potential therapeutic targets for both diseases. The insulin-resistant state, commonly reported in AD brain, results in neuronal glucose deprivation, due to a dampening down of the PI3K/Akt pathway, including overactivity of the mammalian target of rapamycin 1 (mTORC1) complex, hyperphosphorylation of p53 and neuronal death. This contrasts with cancer, where there is overstimulation of the PI3K/Akt pathway and the suppression of mTORC1 and p53, enabling abundant energy and unrestrained cell proliferation. Although these disease states appear to be diametrically opposed, the same key molecules are controlling pathology and, with differential targeting of therapeutics, may yet provide a beneficial outcome for both.

The role of ubiquitination and deubiquitination in cancer metabolism

“…Fatty acids can also supply carbon to the tricarboxylic acid (TCA) cycle to sustain mitochondrial function [ 16 ]. PI3K-AKT signaling is the most well-known mechanism for activating mTORC1 [ 17 ]. Besides, mTORC1 can be activated or inhibited by various signaling pathways directly or indirectly.…”

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“…Moreover, the PI3K/Akt signalling pathway has been conserved to regulate and maintain appropriate cell growth, survival and metabolism (Barker et al. 2020 ), which is an important signalling pathway of insulin action and related to NAFLD progression (Zeng et al. 2014 ).…”

Insulin Receptor Substrate 1 Is Involved in the Phycocyanin-Mediated Antineoplastic Function of Non-Small Cell Lung Cancer Cells

“…The PI3K/AKT signaling pathway is indispensable for cell differentiation, and it has been evolutionarily conserved to maintain appropriate cell growth, survival, and metabolism [ 42 ]. IRS-1 is one of the central mediators in transmitting signals from IGF-IR receptors via the PI3K/AKT pathway and it is commonly overexpressed in cancer [ 43 ]. Meanwhile, Kathryn E et al reported that inhibition of mTOR in tumors caused activation of Akt kinase which is associated with induction of IRS-1 and was prevented by IGF-IR inhibition [ 44 ].…”