Low-dose arsenic induces chemotherapy protection via p53/NF-κB-mediated metabolic regulation

Abstract

Most chemotherapeutical drugs kill cancer cells chiefly by inducing DNA damage, which unfortunately also causes undesirable injuries to normal tissues, mainly due to p53 activation. We report a novel strategy of normal tissue-protection that involves p53/NF-κB coordinated metabolic regulation. Pretreatment of untransformed cells with low doses of arsenic induced concerted p53 suppression and NF-κB activation, which elicited a marked induction of glycolysis. Significantly, this metabolic shift provided cells effective protection against cytotoxic chemotherapy, coupling the metabolic pathway to cellular resistance. Using both in vitro and in vivo models, we demonstrated an absolute requirement of functional p53 in arsenic-mediated protection. Consistently, a brief arsenic-pretreatment selectively protected only normal tissues but not tumors from toxicity of chemotherapy. An indispensable role of glycolysis in protecting normal tissues was demonstrated by using an inhibitor of glycolysis, 2-deoxyglucose, which almost totally abolished low-dose arsenic-mediated protection. Together, our work demonstrates that low-dose arsenic renders normal cells and tissues resistance to chemotherapy-induced toxicity by inducting glycolysis.

A Low-dose Arsenic-induced p53 Protein-mediated Metabolic Mechanism of Radiotherapy Protection

“…The tumor suppressor p53 is universally inactivated in tumor cells by either gene mutation or deregulation (15). We showed previously that treatment of non-transformed cells with low-dose arsenic induces a transient and reversible p53 inhibition (10). Consistently, we found that p53 suppression seemed to be a prerequisite for low-dose arsenic to induce HIF-1␣.…”

“…We observed a robust up-regulation of cellular HIF-1␣ levels induced specifically by low doses of arsenic. Using a combination of pharmacological and genetic approaches, we showed that arsenic-induced HIF-1␣ seemed to be through, at least in part, NFB-dependent transcriptional regulation, which is consistent with the fact that HIF-1␣ is a target gene of NFB (6,7) and the latter is stimulated by arsenic, as shown previously (10). Of significance is the finding that low-dose arsenic-induced HIF-1␣ is specific to non-transformed cells, which may constitute the basis of the observed selective protection of normal tissue.…”

“…We recently reported that treatment with low doses of arsenic induced glycolysis in cells and mice (10). However, the underlying molecular mechanism remained incompletely understood.…”

Low-dose arsenic-mediated metabolic shift is associated with activation of Polo-like kinase 1 (Plk1)

“…6,8 However, the molecular mechanism underlying this intriguing observation is still elusive. To systematically study the low-dose arsenic-associated metabolic shift, we first compared glucose homeostasis of mice fed with 0.01% sodium arsenite-containing water for 16 weeks with age-matched mice that were fed with regular water by performing glucose tolerance test (GTT).…”

“…5 Low-dose arsenic (50 nM for 12 h) actually induces chemotherapy protection, since it causes cytoplasmic accumulation of tumor suppressor p53, thus antagonizing DNA damage-induced p53 response in normal tissues during chemotherapy. [6][7][8] It was further shown that low-dose arsenic-induced chemotherapy protection is due to p53/ NF-kB-mediated metabolic switch from mitochondrial respiration to aerobic glycolysis. 6 Despite these progresses, the detailed mechanisms underlying low-dose Keywords: low-dose arsenic, metabolic shift, NF-kB, Plk1, PI3K/AKT/mTOR pathway Abbreviations: Dox, doxorubicin; ECAR, extracellular acidification rate; GTT, glucose tolerance test; mTOR1, mammalian target of rapamycin complex I; MEF, mouse embryo fibroblast; PDTC, pyrrolidine dithiocarbamate; PI3K, phosphatidylinositol 3-kinase; Plk1, polo-like kinase 1; PTEN, phosphatase and tensin homolog; Plk1-iKD, Plk1-inducible knockdown; 2-DG, 2-deoxy-glucose.…”