Caspases and cancer: mechanisms of inactivation and new treatment modalities

Area of Science:

• Cell Biology
• Molecular Oncology
• Biochemistry

Background:

• Apoptosis, or programmed cell death, is a fundamental biological process for removing superfluous or mutated somatic cells.
• Dysregulation of apoptotic signaling pathways is increasingly recognized as a significant contributor to oncogenesis.
• Caspases, aspartate-specific cysteine proteases, are central effector molecules executing the apoptotic cascade.

Purpose of the Study:

• To review identified defects in the caspase-dependent cell death machinery within neoplastic cells.
• To highlight molecular alterations contributing to impaired apoptosis in cancer.
• To discuss emerging therapeutic strategies targeting apoptosis in cancer treatment.

Main Methods:

• Literature review of studies investigating defects in apoptosis-related genes and proteins in cancer.
• Analysis of molecular mechanisms including genetic mutations, epigenetic alterations (gene methylation), and mRNA instability.
• Examination of components from both extrinsic (e.g., CD95, FADD, FLIPs) and intrinsic (e.g., Apaf-1, caspase-9) apoptotic pathways.

Main Results:

• Neoplastic cells exhibit diverse defects in apoptosis, including mutations in caspases and related proteins.
• Epigenetic modifications and altered mRNA stability of apoptosis regulators are prevalent in various cancers.
• Key molecules involved in both extrinsic and intrinsic pathways, as well as apoptosis modulators (IAPs, Smac/DIABLO), are frequently dysregulated.

Conclusions:

• Defects in the caspase-dependent apoptosis machinery are a hallmark of cancer, promoting tumor development and progression.
• Targeting these apoptotic defects with novel cancer-specific agents holds therapeutic promise.
• Combining apoptosis-activating strategies with conventional cancer therapies may enhance treatment efficacy.