Andrographolide induces degradation of mutant p53 via activation of Hsp70

Area of Science:

• Molecular Biology
• Oncology
• Pharmacology

Background:

• The p53 gene is a critical tumor suppressor, regulating DNA repair, apoptosis, and cell cycle.
• Mutations in p53 are found in about half of human cancers, leading to oncogenic functions.
• Targeting mutant p53 is a promising strategy for anticancer therapies.

Purpose of the Study:

• To identify small molecules that suppress mutant p53.
• To investigate the effects of andrographolide (ANDRO) on cancer cells with wild-type or mutant p53.
• To elucidate the molecular mechanisms underlying ANDRO's action on mutant p53.

Main Methods:

• Small-molecule screening to identify mutant p53 suppressors.
• Treatment of tumor cells (wild-type and mutant p53) with ANDRO.
• Analysis of gene and protein expression, including p53, p21, pro-apoptotic genes, and Hsp70.
• Assessment of cancer cell growth inhibition.

Main Results:

• Andrographolide (ANDRO) suppressed mutant p53 expression.
• ANDRO induced p21 and pro-apoptotic gene expression, inhibiting growth of mutant p53 cancer cells.
• ANDRO upregulated heat-shock protein 70 (Hsp70), enhancing its binding to mutant p53 and promoting proteasomal degradation.

Conclusions:

• Andrographolide (ANDRO) effectively targets and suppresses mutant p53.
• ANDRO's mechanism involves Hsp70-mediated degradation of mutant p53.
• Hsp70 activation presents a novel therapeutic strategy for cancers with mutant p53.