Niacin deficiency alters p53 expression and impairs etoposide-induced cell cycle arrest and apoptosis in rat bone marrow cells.
One focus of chemoprevention research is the interaction of nutrients with specific molecular targets associated with the maintenance of genomic stability. This study tested the impact of dietary niacin status on bone marrow NAD+ and poly(ADP-ribose) (pADPr) levels, p53 expression, and etoposide (ETO)-induced apoptosis and cell cycle arrest. After 3 wk on niacin-deficient (ND), pair-fed niacin-replete (PF), or nicotinic acid-supplemented (4 g/kg diet) (NA) diets, Long-Evans rats were gavaged with ETO (25 mg/kg) or vehicle. ND and NA diets caused a 72% decrease and a 240% increase in bone marrow NAD+, respectively. Basal and ETO-induced pADPr levels differed dramatically among ND, PF, and NA diets (undetectable, 42 and 216 fmol/million cells, respectively; basal and undetectable, 119 and 484 fmol/million cells, respectively, following ETO). ND diet alone caused overexpression of two distinct isoforms of p53. Levels of p53 in PF and NA marrow increased in response to ETO treatment, but this did not occur in ND bone marrow. Quantitative polymerase chain reaction of regular and alternative spliced variants of p53 mRNA revealed that niacin deficiency actually decreased both forms of p53 message, implicating protein stability in the accumulation of p53 in ND marrow. ETO-induced apoptosis (TUNEL) was suppressed during niacin deficiency and enhanced by supplementation. G1 arrest was also impaired in ND bone marrow relative to PF and NA. Despite a poor G1 arrest, p21waf1 was overexpressed in the ND bone marrow and dramatically induced following ETO treatment. In conclusion, dietary niacin deficiency causes changes in NAD+ and pADPr metabolism, alters p53 expression, and impairs cellular responses to DNA damage.
Spronck
Jennifer C
JC
Department of Human Biology and Nutritional Sciences, University of Guelph, Ontario, Canada.
Nickerson
Jennifer L
JL
Kirkland
James B
JB
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D005047:Etoposide / Q000494:pharmacology*; D016158:Genes, p53 / Q000187:drug effects*; D020287:In Situ Nick-End Labeling; D009243:NAD / Q000378:metabolism; D009525:Niacin / Q000008:administration & dosage / Q000172:deficiency; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D011897:Random Allocation; D051381:Rats; D020318:Rats, Long-Evans; D014803:Vitamin B Complex / Q000008:administration & dosage; D014804:Vitamin B Deficiency
D000972:Antineoplastic Agents, Phytogenic; D009243:NAD; D014803:Vitamin B Complex; D011064:Poly Adenosine Diphosphate Ribose; D009525:Niacin; D005047:Etoposide