ABSTRACT
Mammalian target of rapamycin (mTOR) controls cellular anabolism, and mTOR signaling is hyperactive in most cancer cells. As a result, inhibition of mTOR signaling benefits cancer patients. Rapamycin is a US Food and Drug Administration (FDA)-approved drug, a specific mTOR complex 1 (mTORC1) inhibitor, for the treatment of several different types of cancer. However, rapamycin is reported to inhibit cancer growth rather than induce apoptosis. Pyruvate dehydrogenase complex (PDHc) is the gatekeeper for mitochondrial pyruvate oxidation. PDHc inactivation has been observed in a number of cancer cells, and this alteration protects cancer cells from senescence and nicotinamide adenine dinucleotide (NAD+) exhaustion. In this paper, we describe our finding that rapamycin treatment promotes pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) phosphorylation and leads to PDHc inactivation dependent on mTOR signaling inhibition in cells. This inactivation reduces the sensitivity of cancer cells' response to rapamycin. As a result, rebooting PDHc activity with dichloroacetic acid (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, promotes cancer cells' susceptibility to rapamycin treatment in vitro and in vivo.
Subject(s)
Humans , Sirolimus/pharmacology , Dichloroacetic Acid/pharmacology , Pyruvate Dehydrogenase Complex , TOR Serine-Threonine Kinases , Mechanistic Target of Rapamycin Complex 1 , Neoplasms/drug therapyABSTRACT
AIM: To investigate the effects of baicalein(BAI)on the proliferation and migration of gastric cancer MGC-803 cells and the mechanisms.METHODS:After MGC-803 cells were treated with BAI at different concen-trations,the viability of the MGC-803 cells was tested by MTT assay.The cell colony formation ability were detected by plate colony formation assay.Wound-healing and Transwell cell migration assays were used to test the migration ability of the MGC-803 cells.The concentration of 12-hydroxyeicosatetraenoic acid(12-HETE)was measured by ELISA.The pro-tein levels of platelet type 12-lipoxygenase(p12-LOX),vascular endothelial growth factor(VEGF),p-ezrin and epithelial-mesenchymal transition(EMT)markers in MGC-803 cells were determined by Western blot.RESULTS:BAI significantly inhibited the proliferation,plate colony formation and migration abilities of the MGC-803 cells(P<0.05 or P<0.01), down-regulated the concentration of p12-LOX metabolite 12-HETE significantly(P<0.05 or P<0.01), decreased the protein levels of p12-LOX,VEGF,p-ezrin,vimentin and Snail(P<0.05 or P<0.01),and increased the protein expres-sion of E-cadherin(P<0.01).CONCLUSION:BAI suppresses the proliferation and migration abilities of gastric cancer MGC-803 cells effectively.These effects of BAI may be related to regulating the protein levels of p12-LOX,VEGF,p-ezrin and EMT-related proteins.
ABSTRACT
OBJECTIVE: To study the effect of Boschniakia rossica extract on free radicals in the brain of D-galactose induced senile rats. METHODS: Sixty Wistar rats were randomly divided into normal group, model group (48 mg.kg(-1).d(-1) D-galactose, SC), Boschniakia rossica group (100, 150, 200 mg/kg ig and 48 mg.kg(-1).d(-1) D-galactose, SC). After 40 days, the activities of SOD, MAO and the content of MDA were measured with colorimetric method, and the histological changes were synchronously observed by electronic microscope. RESULTS: Boschniakia rossica extract significantly increased the SOD activity, decreased the MDA content, and inhibited the MAO activity in the brain tissue. It was observed under microscope that Boschniakia rossica extract could retrieve the degeneration of mitochondrion. CONCLUSION: Boschniakia rossica extract can clear the free radicals for D-galactose induced senile rats.