An acid test for metformin.

Lactic acid export from highly glycolytic cancer cells is critical to maintain cellular homeostasis. The identification of syrosingopine as an inhibitor of the lactate transporters monocarboxylate transporter (MCT) 1 and the tumor-induced isoform MCT4 suggests a potential therapeutic intervention. In a recent issue of this journal, Van der Vreken, Oudaert I and colleagues showed that syrosingopine, together with another drug metformin, had a synergistic effect in killing cultured multiple myeloma (MM) cell lines, primary MM blasts from patients, and in a mouse MM model.

Combining metformin with lactate transport inhibitors as a treatment modality for cancer - recommendation proposal.

Highly glycolytic cancer cells excrete lactate to maintain cellular homeostasis. Inhibiting lactate export by pharmacological targeting of plasma membrane lactate transporters is being pursued as an anti-cancer therapy. Work from many laboratories show that the simultaneous inhibition of lactate export and mitochondrial respiration elicits strong synthetic lethality.

mTOR substrate phosphorylation in growth control.

The target of rapamycin (TOR), discovered 30 years ago, is a highly conserved serine/threonine protein kinase that plays a central role in regulating cell growth and metabolism. It is activated by nutrients, growth factors, and cellular energy. TOR forms two structurally and functionally distinct complexes, TORC1 and TORC2.

Lack of benefit from low dose computed tomography in screening for lung cancer - comment on paper by Huang K-L et al.

The article by Huang K-L et al. Effects of low-dose computed tomography (LDCT) screening on lung cancer contains a conclusion that is not consistent with the data presented. With reference to the National Lung Screening Trial (NLST) there are several flaws in the methodology overlooked.

Lactate jump-starts mTORC1 in cancer cells.

The kinase mammalian target of rapamycin (mTOR) is a major regulatory hub that senses and integrates nutrient, energy, and growth factor inputs to promote cell growth. In this issue of , Byun [1] report that high intracellular levels of lactate activate mTORC1 in KRAS transformed cells independently of a growth factor input. This suggests a mechanism for how mTORC1 can be co‐opted to support oncogenic growth and proliferation.

mTORC1 Controls Synthesis of Its Activator GTP.

In this issue of Cell Reports, Emmanuel et al. (2017) report that mTORC1 activity is regulated by purine availability. This increases the number of mTORC1 regulators to include metabolites whose synthesis mTORC1 controls.

Syrosingopine sensitizes cancer cells to killing by metformin.

We report that the anticancer activity of the widely used diabetic drug metformin is strongly potentiated by syrosingopine. Synthetic lethality elicited by combining the two drugs is synergistic and specific to transformed cells. This effect is unrelated to syrosingopine's known role as an inhibitor of the vesicular monoamine transporters.

mTORC1: turning off is just as important as turning on.

mTORC1 is activated primarily on the lysosome. Menon et al. and Demetriades et al.

TSC on the peroxisome controls mTORC1.

mTOR is a central controller that integrates many inputs to regulate cell growth and ensure cellular homeostasis. The mTORC1 inhibitor TSC (tuberous sclerosis complex) on the peroxisome is found to inhibit mTORC1 in response to endogenous reactive oxygen species. Thus, mTOR may avoid confounding different inputs by sensing them at different cellular locations.

Rapamycin passes the torch: a new generation of mTOR inhibitors.

Mammalian target of rapamycin (mTOR) is an atypical protein kinase that controls growth and metabolism in response to nutrients, growth factors and cellular energy levels, and it is frequently dysregulated in cancer and metabolic disorders. Rapamycin is an allosteric inhibitor of mTOR, and was approved as an immuno-suppressant in 1999. In recent years, interest has focused on its potential as an anticancer drug.

mRNA stability and cancer: an emerging link?

Many oncogenes, growth factor, cytokine and cell-cycle genes are regulated post-transcriptionally. The major mechanism is by controlling the rate of mRNA turnover for transcripts bearing destabilizing cis-elements. To date, only a handful of regulatory factors have been identified that appear to control a large pool of target mRNAs, suggesting that a slight perturbation in the control mechanism may generate wide-ranging effects that could contribute to the development of a complex disorder such as cancer.

A GFP-based assay for monitoring post-transcriptional regulation of ARE-mRNA turnover.

Interleukin-3 (IL3) mRNA is intrinsically labile due to the presence of a destabilizing AU-rich element (ARE) that targets the transcript for rapid degradation. We review our experience with a sensitive reporter system where changes in IL3 mRNA stability are translated into increased/decreased green fluorescent protein (GFP) signals. A GFP reporter gene was fused to the full-length IL3 3'UTR containing the ARE motif that responds to regulatory signals that control transcript stability.

BRF1 protein turnover and mRNA decay activity are regulated by protein kinase B at the same phosphorylation sites.

BRF1 posttranscriptionally regulates mRNA levels by targeting ARE-bearing transcripts to the decay machinery. We previously showed that protein kinase B (PKB) phosphorylates BRF1 at Ser92, resulting in binding to 14-3-3 and impairment of mRNA decay activity. Here we identify an additional regulatory site at Ser203 that cooperates in vivo with Ser92.

A GFP-based assay for rapid screening of compounds affecting ARE-dependent mRNA turnover.

A reporter transcript containing the green fluorescent protein (GFP) gene upstream of the destabilizing 3'-untranslated region (3'-UTR) of the murine IL-3 gene was inserted in mouse PB-3c-15 mast cells. The GFP-IL-3 transcript was inherently unstable due to the presence of an adenosine-uridine (AU)-rich element (ARE) in the 3'-UTR and was subject to rapid decay giving a low baseline of GFP fluorescence. Transcript stabilization with ionomycin resulted in an increase of fluorescence that is quantitated by FACS analysis of responding cells.