Metformin has utility in cancer prevention and treatment, though the mechanisms for these effects remain elusive. Through genetic screening in C. elegans, we uncover two metformin response elements: the nuclear pore complex (NPC) and acyl-CoA dehydrogenase family member-10 (ACAD10). We demonstrate that biguanides inhibit growth by inhibiting mitochondrial respiratory capacity, which restrains transit of the RagA-RagC GTPase heterodimer through the NPC. Nuclear exclusion renders RagC incapable of gaining the GDP-bound state necessary to stimulate mTORC1. Biguanide-induced inactivation of mTORC1 subsequently inhibits growth through transcriptional induction of ACAD10. This ancient metformin response pathway is conserved from worms to humans. Both restricted nuclear pore transit and upregulation of ACAD10 are required for biguanides to reduce viability in melanoma and pancreatic cancer cells, and to extend C. elegans lifespan. This pathway provides a unified mechanism by which metformin kills cancer cells and extends lifespan, and illuminates potential cancer targets. PAPERCLIP.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390486 | PMC |
| http://dx.doi.org/10.1016/j.cell.2016.11.055 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Unlabelled: As the principal lipid transporter in the human brain, apolipoprotein E (ApoE) is tasked with the transport and protection of highly vulnerable lipids required to support and remodel neuronal membranes, in a process that is dependent on ApoE receptors. Human allele variants that encode proteins differing only in the number of cysteine (Cys)-to-arginine (Arg) exchanges (ApoE2 [2 Cys], ApoE3 [1 Cys], ApoE4 [0 Cys]) comprise the strongest genetic risk factor for sporadic Alzheimer's disease (AD); however, the molecular feature(s) and resultant mechanisms that underlie these isoform-dependent effects are unknown. One signature feature of Cys is the capacity to form disulfide (Cys-Cys) bridges, which are required to form disulfide bridge-linked dimers and multimers.
View Article and Find Full Text PDFContemporary clinical perspectives on chronic low back pain: The biology, mechanics, etc. underpinning clinical and radiological evaluation.
JOR Spine
March 2025
Spine Labs St George and Sutherland Clinical School, University of New South Wales Kogarah New South Wales Australia.
Background: Pain of a chronic nature remains the foremost concern in tertiary spine clinics, yet its elusive nature and quantification challenges persist. Despite extensive research and education on low back pain (LBP), the realm of diagnostic practices lacks a unified approach. Clinically, LBP exhibits a multifaceted character, encompassing conventional assessments of severity and disability, alongside nuanced attributes like pain characterization, duration, and patient expectations.
View Article and Find Full Text PDFSleep and circadian rhythms modeling: From hypothalamic regulatory networks to cortical dynamics and behavior.
Handb Clin Neurol
January 2025
School of Physics, Faculty of Science, University of Sydney, Camperdown, NSW, Australia.
Sleep and circadian rhythms are regulated by dynamic physiologic processes that operate across multiple spatial and temporal scales. These include, but are not limited to, genetic oscillators, clearance of waste products from the brain, dynamic interplay among brain regions, and propagation of local dynamics across the cortex. The combination of these processes, modulated by environmental cues, such as light-dark cycles and work schedules, represents a complex multiscale system that regulates sleep-wake cycles and brain dynamics.
View Article and Find Full Text PDFBackground：Neurological deterioration following acute ischemic stroke (AIS) is a common clinical phenomenon associated with poor clinical outcomes. However, neurological deterioration can be attributed to diverse mechanisms in different clinical contexts. Further, there is still a lack of standard and well-recognized definitions of neurological deterioration, which compounds the complexities and challenges of its early identification and management of neurological deterioration.
View Article and Find Full Text PDFThe association between Chlamydia pneumoniae infection and prognosis in lung cancer patients: a prospective study.
BMC Infect Dis
January 2025
Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, China.
Background: The prognostic value of Chlamydia pneumoniae (Cpn) infection in postoperative lung cancer patients remains unclear. This study aimed to evaluate the association between Cpn infection and survival in lung cancer patients.
Methods: This study included 309 newly diagnosed primary lung cancer patients from three hospitals in Fuzhou, China.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!