Pan-BH3 mimetic S1 exhibits broad-spectrum antitumour effects by cooperation between Bax and Bak

Area of Science:

• Molecular Biology
• Cancer Research
• Cell Death Pathways

Background:

• Antiapoptotic B-cell lymphoma 2 (Bcl-2) proteins (Bcl-2, Bcl-xL, Mcl-1) are crucial regulators of apoptosis.
• BH3 mimetics are a class of drugs designed to inhibit these antiapoptotic proteins, thereby promoting cancer cell death.
• Understanding the specific interactions and downstream effects of novel BH3 mimetics is essential for cancer therapy development.

Purpose of the Study:

• To investigate the mechanism of apoptosis induction by small molecule S1, a pan-BH3 mimetic.
• To compare the anticancer spectrum and apoptotic cascade of S1 with the Bcl-2/Bcl-xL inhibitor ABT-737.
• To elucidate the roles of Bax and Bak in S1-induced apoptosis.

Main Methods:

• Utilized cancer cell lines with varying Bcl-2 family member expression (NCI-H345, MCF-7, SMMC-7721, Hela).
• Employed short hairpin RNA (shRNA) to create cells deficient in Bax and/or Bak.
• Analyzed apoptotic pathways and protein interactions induced by S1 and ABT-737.

Main Results:

• Small molecule S1 demonstrated a broader antitumour spectrum than ABT-737, disrupting additional Bcl-2 interactions, including Mcl-1/Bak.
• S1-induced apoptosis was predominantly mediated by Bak.
• Both S1 and ABT-737-induced apoptosis relied on Bak, with Bax cooperating in the formation of large mitochondrial membrane oligomers.

Conclusions:

• Small molecule S1 is a potent pan-BH3 mimetic with superior anticancer activity compared to ABT-737 due to its broader target engagement.
• Bak plays a critical and predominant role in S1-induced apoptosis, working in conjunction with Bax.
• These findings highlight S1 as a promising therapeutic agent and underscore the importance of Bak in mediating apoptosis induced by BH3 mimetics.