Lamins are important constituents of the nuclear inner membrane and provide a 
platform for transcription factors and chromatin. Progerin, a C-terminal 
truncated lamin A mutant, causes premature aging termed Hutchinson-Gilford 
Progeria Syndrome (HGPS). Oxidative stress appears to be involved in the 
pathogenesis of HGPS, although the mechanistic role of progerin remains elusive. 
Here we examined whether nuclear lamins are important for a cellular antioxidant 
mechanism, and whether progerin compromises it. We investigated the activation 
of nuclear factor-E2-related factor 2 (Nrf2) which regulates various antioxidant 
genes including heme oxygenase-1 (HMOX1), following exposure to sodium arsenite 
or cadmium chloride in lamin knockdown human cell lines and primary HGPS human 
fibroblasts. Knocking down lamin A/C, or B, or all nuclear lamins simultaneously 
in three human cell lines (HaCaT, SW480, and K562) did not impair arsenite- or 
cadmium-induced activation of Nrf2. Progerin-expressing human primary HGPS 
fibroblasts showed lower basal levels of HMOX1 and NQO1 expression; however, in 
response to arsenic stress both normal and HGPS primary fibroblasts showed Nrf2 
nuclear accumulation along with upregulation and phosphorylation of p62/SQSTM1 
at Ser351, downregulation of Keap1, and comparable expression of an array of 
downstream Nrf2-regulated antioxidant genes. We also observed new forms of 
cleaved lamin A, B1 and B2 induced by cadmium stress although their roles in the 
Nrf2 antioxidant system need further investigation. These results suggest that 
the nuclear lamins and progerin have marginal roles in the activation of the 
antioxidant Nrf2 response to arsenic and cadmium.