p53 (Tumor protein P53; cellular tumor antigen p53; transformation-related protein 53 (TRP53)) is a regulatory protein. The p53 proteins are crucial in vertebrates, where they prevent cancer formation. As such, p53 is “the guardian of the genome” because of its role in conserving stability by preventing genome mutation. Hence TP53 belongs to a tumor suppressor gene. The TP53 gene is the most frequently mutated gene (>50%) in human cancer. Therefore, TP53 gene plays a crucial role in preventing cancer formation. TP53 gene encodes proteins that bind to DNA and regulate gene expression to prevent mutations of the genome. In addition to the full-length protein, the human TP53 gene encodes at least 15 protein isoforms.
The p53 tumor suppressor is a principal mediator of growth arrest, senescence, and apoptosis in response to a broad array of cellular damage. Under stress conditions, the p53 protein accumulates in the cell, binds in its tetrameric form to p53-response elements and induces the transcription of various genes. p53 can transcriptionally activate MDM-2 and MDM-2, in turn, inhibits p53 activity in several ways. MDM-2 binds to the p53 transactivation domain and thereby inhibits p53-mediated transactivation. In many tumors p53 is inactivated by the overexpression of the negative regulators MDM2 and MDM4 or by the loss of activity of the MDM2 inhibitor ARF.
SLMP53-2 is a mutant p53 reactivator.
SLMP53-2 restores wild-type-like conformation and DNA-binding ability of mutp53-Y220C by enhancing its interaction with the Hsp70, leading to the reestablishment of p53 transcriptional activity. Therefore, SLMP53-2 can induce cell cycle arrest, apoptosis and endoplasmic reticulum (ER) stress. SLMP53-2 inhibits the growth of HuH-7 and HCC1419 cells with similar IC50 values. Meanwhile, SLMP53-2 shows significantly lower growth inhibitory activity against non-tumoral HFF-1 cells. Besides, SLMP53-2 induces G0/G1-phase cell cycle arrest and apoptosis in HuH-7 cells. SLMP53-2 displays a concentration-dependent growth inhibitory effect on colony formation in HuH-7 cells. Moreover, LMP53-2 sensitizes HuH-7 cells to Sorafenib.
All in all, SLMP53-2 is a new mutp53-targeting agent with promising antitumor activity.