New study shows AMPK activator MG132 rescues Progeria cells, protects against Microgravity, & inhibits Cancer Stem Cells, HIV, Dengue, & Malaria

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A recent study published online in the journal EMBO Molecular Medicine in July of 2017 strikingly demonstrated that the proteasome inhibitor and AMPK activator MG132 alleviated accelerated aging defects in cells derived from children with the genetic disorder Hutchinson-Gilford progeria syndrome(HGPS) by inducing autophagic degradation of progerin, the toxic protein responsible for accelerated aging defects in HGPS cells [1]. MG132 also beneficially altered splicing of the LMNA gene (a gene that is aberrantly spliced to produce large amounts of progerin instead of the normal lamin A gene product) by decreasing the gene splicing factor SRSF1 but increasing the splicing factor SRSF5 [1]. Interestingly, progerin was shown to accumulate in structures known as promyelocytic nuclear bodies (PML-NBs) in the nucleus of HGPS cells and local injection of MG132 into a progeria mouse model also led to a reduction in the levels of SRSF1 and progerin [1]. Intriguingly, normal humans also produce progerin via the same aberrant gene splicing method as do children with HGPS, just at much lower levels that increase with age [2].

The recent finding that MG132-induced proteasome inhibition also results in a rapid activation of the master metabolic regulator AMPK (a kinase that increases lifespan and healthspan in several model organisms) and AMPK-dependent autophagy stimulation via the induction of cellular stress (i.e. reactive oxygen species [ROS] generation) further substantiates my hypothesis published in 2014 in which I was first to propose that AMPK activation by structurally diverse compounds (e.g. metformin, resveratrol, etc.) will lead to alleviation of accelerated aging defects in HGPS cells by decreasing the gene splicing factor SRSF1, thus beneficially altering splicing of the LMNA gene, as well as decreasing progerin levels by AMPK-induced autophagy [3,4,33].

Indeed, metformin, which induces cellular stress by mildly inhibiting complex I of the electron transport chain (thus increasing the AMP/ATP ratio) has also recently been shown to reduce the levels of SRSF1 and progerin and activate AMPK in HGPS cells [5-7]. Platelet-derived growth factor BB (PDGF-BB) also increases intracellular calcium (Ca2+) and ROS levels (mediators of cellular stress induction), activates AMPK, and increases SRSF5 in HGPS cells, thus altering splice site selection and beneficially increasing the lamin A/progerin ratio, providing compelling evidence that cellular stress-induced AMPK activation indeed represents a common mechanism of action for gene splicing- and autophagy-induced reductions of progerin in HGPS cells [8-10].

Interestingly, SRSF1 (also known as ASF/SF2) and PML-NBs also inhibit latent HIV-1 reactivation (preventing immune system detection and virus eradication) and SRSF5 (also known as SRp40) increases the abundance and translation of unspliced HIV-1 RNA, which is necessary for latent HIV-1 reactivation [11-13]. As AMPK promotes both latent HIV-1 reactivation and prevents HIV-1 transactivation, MG132 has been shown to reactivate latent HIV-1 and inhibit HIV-1 replication, substantiating my hypothesis published in 2015 in which I first proposed that AMPK activation links correction of aberrant alternative splicing in HGPS cells with reactivation of latent HIV-1 by compounds including MG132, metformin, and resveratrol [14-18].

Additionally, as the induction of cellular stress (e.g. intracellular Ca2+ increase, ROS generation, AMP/ATP ratio increase, etc.) activates AMPK, reactivates latent HIV-1, and leads to the differentiation and/or apoptosis of cancer stem cells in an AMPK-dependent manner, MG132 has also recently been found to induce apoptosis in glioma cancer stem cells, substantiating my most recent publication (2017) in which I propose for the first time that AMPK activation links reactivation of latent HIV-1 with cancer stem cell differentiation and/or apoptosis by diverse compounds that induce cellular stress including metformin and MG132 [5,19-23].

MG132 also induces mouse oocyte meiotic resumption (a process orchestrated by cellular stress-induced AMPK activation and is critical for efficient oocyte activation), delays in vitro oocyte aging, promotes embryonic development from aged oocytes after in vitro fertilization procedures, and alleviates deleterious effects associated with simulated microgravity, further supporting my hypotheses in 2016 and 2017 in which I first proposed that cellular stress-induced AMPK activation links oocyte activation (and hence the beginning of all human life) with latent HIV-1 reactivation and that AMPK activation will improve the activation of T cells in simulated microgravity/spaceflight (which is dependent on intracellular increases in Ca2+ and ROS) [23-28].

As AMPK activators including metformin and MG132 also inhibit dengue virus replication and malaria parasite growth, the aforementioned studies strongly suggests the novel observation that AMPK activation represents a common mechanism of action linking chemically distinct compounds and the effects of those compounds in diseases and phenomena as seemingly disparate as HGPS, HIV-1, microgravity/spaceflight, cancer stem cells, dengue fever, and malaria [29-32]. 

https://www.linkedin.com/pulse/new-study-shows-ampk-activator-mg132-rescues-progeria-finley?published=t

References

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