Curcumin induces apoptosis via downregulation of SKP2 and induction of GADD45A/CDKN1A expression through generation of ROS in cutaneous T-cell lymphoma cells

Curcumin, a plant derived natural product isolated from Curcuma longa. The aim of this study is to investigate the anti-proliferative effects and the underlying mechanisms of curcumin in Cutaneous T cell lymphoma (CTCL), a type of non-Hodgkin lymphoma that primarily affects the skin. The study found that curcumin induced apoptosis in CTCL cells by activating mitochondrial signaling pathways and caspases leading to growth inhibition. Furthermore, Curcumin treatment downregulated the expression of S-phase kinase protein (SKP2) with concomitant upregulation of GADD45A, CDKN1A and CDKN1B. Curcumin also suppresses the expression of anti-apoptotic molecules including XIAP and cIAPs. Curcumin treatment of CTCL cells generates reactive oxygen species (ROS) and depletion of glutathione. Pretreatment of CTCL with N-acetyl cysteine prevented curcumin-mediated generation of ROS and prevention caspase activity. Co-treatment of CTCL with subtoxic doses of curcumin and bortezomib potentiated the anticancer action. Co-treatment of CTCL with subtoxic doses of curcumin and bortezomib potentiated the anticancer action. Molecular docking studies revealed a strong binding affinity of curcumin to the active site of SKP2, primarily involving key residues crucial for its activity. Altogether, our results suggest that targeting SKP2 and GADD45A signaling by curcumin could be an attractive strategy for the treatment of CTCL.