Harnessing PUMA's lethal potential: BCL-2 family dynamics and novel strategies to combat cancer recurrence.

Abstract

Cancer cells often survive treatment by blocking the natural process of cell death, allowing them to return and grow again. The BCL-2 protein family plays a central role in this process, controlling whether a cell lives or dies. Among its members, the BH3-only proteins initiate the apoptotic cascade in response to cellular stress. PUMA (p53-upregulated modulator of apoptosis), a pro-apoptotic BH3-only protein, is the most potent of its subclass, binding all major anti-apoptotic BCL-2 family members (Bcl-xL, Bcl-2, Mcl-1, and Bcl-w) to counteract their inhibition of Bax and Bak. Upon activation, Bax/Bak form pores in the mitochondrial membrane, releasing apoptogenic factors such as cytochrome c, SMAC, and apoptosis-inducing factor, ultimately triggering caspase-mediated cell death. Due to its upstream role in apoptosis, PUMA deficiency or inhibition by anti-apoptotic proteins promotes cancer development and therapy resistance. Conversely, elevated PUMA expression sensitizes cancer cells to chemo- and radiotherapy. Accumulating evidence positions PUMA as a universal sensor of cell death stimuli and a promising therapeutic target in cancer. This article critically examines PUMA's regulation, function, and potential as a target for cancer treatment.