A new era in cancer therapy: targeting the Proteasome-Bcl-2 axis

Sep 24, 2026

Uploaded by Kurz

B-cell lymphoma-2 (Bcl-2) family proteins are central apoptosis regulators, often dysregulated in cancer to favor survival over cell death. The ubiquitin-proteasome system (UPS) controls Bcl-2 levels by regulating protein stability, linking proteasome function to apoptotic balance. This review analyzes the proteasome–Bcl-2 interplay, explaining how proteasome-mediated degradation influences cancer cell survival and proliferation. It evaluates proteasome inhibitor anticancer strategies, detailing mechanisms, clinical efficacy, limitations, and emerging approaches to overcome resistance.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages30

Reading Time1 h 16 min

AccessFree to download

Background

Apoptosis and disease relevance

Bcl-2 family proteins in apoptosis

Balance between anti-apoptotic and pro-apoptotic members

Cancer-related dysregulation

Ubiquitin-proteasome system (UPS)

Protein stability via ubiquitination and degradation

Soni etal. Journal of Experimental & Clinical Cancer Research (2025) 44:246 [https://doi.org/10.1186/s13046-025-03505-5](https://doi.org/10.1186/s13046-025-03505-5) Journal of Experimental & Clinical Cancer Research REVIEW Open Access A new era in cancer therapy: targeting the Proteasome-Bcl-2 axis Sourabh Soni 1, Vandana Anang 1, Yutong Zhao 1,2, Jeffrey C. Horowitz 1, Richard S. Nho 1* andYohannes A. Mebratu 1* Abstract The B-cell lymphoma-2 (Bcl-2) family proteins, key regulators of apoptosis, are frequently dysregulated in cancer, tipping the balance of cell survival and apoptosis in favor of survival. The ubiquitin-proteasome system (UPS) is a critical cellular machinery that controls the Bcl-2 levels through regulation of protein stability. This review delves into the intricate interplay between the proteasome and Bcl-2 family members, exploring how proteasomemediated degradation impacts cell survival and proliferation to influence cancer progression. We discuss the therapeutic potential of targeting the proteasome-Bcl-2 axis, including the use of proteasome inhibitors as anticancer agents. We examine their mechanisms of action, clinical efficacy, and limitations while exploring emerging strategies to overcome these challenges. Keywords Apoptosis, Bcl-2 family proteins, Cancer, Proteasome inhibitors, Therapeutic potential, Ubiquitination, Ubiquitin-proteasome system (UPS) Background Programmed cell death, or apoptosis, is a tightly controlled process crucial for maintaining cellular homeostasis. This fundamental biological process plays a critical role in a myriad of physiological processes, including embryonic development [1], tissue remodeling [2], and immune response [3]. A delicate balance between cell survival and death is essential for proper tissue function. Imbalances in this equilibrium can contribute to a range of human diseases, such as cancer, neurodegenerative disorders, fibrotic and autoimmune diseases. *Correspondence: Richard S. Nho [Richard.Nho@osumc.edu](Richard.Nho@osumc.edu)[ ](Richard.Nho@osumc.edu)Yohannes A. Mebratu [Yohannes.Mebratu@osumc.edu](Yohannes.Mebratu@osumc.edu) 1Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Davis Heart and Lung Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA 2Department of Physiology and Cell Biology, Davis Heart and Lung Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA Central to the regulation of apoptosis is the B-cell lymphoma-2 (Bcl-2) family of proteins [4]. This family comprises both anti-apoptotic (pro-survival) and proapoptotic members, which interact to maintain a delicate balance between cell survival and death (Table 1) [5]. Figure 1 illustrates how these proteins function downstream of cellular stress signals to govern mitochondrial outer membrane permeabilization and activation of the intrinsic apoptotic pathway. In cancer, this delicate balance is often skewed, allowing tumor cells to evade apoptosis and proliferate unchecked. This evasion frequently involves the dysregulation of Bcl-2 family proteins. Anti-apoptotic members are commonly overexpressed in cancer cells, actively inhibiting apoptosis and promoting tumor growth, while pro-apoptotic members may be downregulated or inactivated, further contributing to cancer cell survival and unchecked proliferation [6]. The ubiquitin-proteasome system (UPS) is a vital cellular machinery that regulates protein stability by tagging proteins for degradation through ubiquitination. In the context of apoptosis, the UPS plays a pivotal role © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a l

FAQs

Why are Bcl-2 family proteins important in cancer?

Bcl-2 family proteins regulate apoptosis by balancing cell survival and death. Cancer often disrupts this balance through overexpression of anti-apoptotic members and loss or inactivation of pro-apoptotic members.

How does the ubiquitin-proteasome system (UPS) relate to Bcl-2?

The UPS regulates Bcl-2 levels by controlling protein stability through ubiquitination and proteasome-mediated degradation.

What therapeutic strategy does the review focus on?

The review focuses on targeting the proteasome-Bcl-2 axis, particularly using proteasome inhibitors as anticancer agents and assessing their mechanisms, clinical efficacy, limitations, and emerging ways to address challenges.

Sep 24, 2026

Uploaded by Kurz