Giunco Silvia, Petrara Maria Raffaella, Indraccolo Stefano, Ciminale Vincenzo, De Rossi Anita
Section of Oncology and Immunology, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
Immunology and Diagnostic Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy.
Cancers (Basel). 2025 Mar 30;17(7):1165. doi: 10.3390/cancers17071165.
The reactivation of telomerase enables cancer cells to maintain the telomere length, bypassing replicative senescence and achieving cellular immortality. In addition to its canonical role in telomere maintenance, accumulating evidence highlights telomere-length-independent functions of TERT, the catalytic subunit of telomerase. These extratelomeric functions involve the regulation of signaling pathways and transcriptional networks, creating feed-forward loops that promote cancer cell proliferation, resistance to apoptosis, and disease progression. This review explores the complex mechanisms by which TERT modulates key signaling pathways, such as NF-κB, AKT, and MYC, highlighting its role in driving autonomous cancer cell growth and resistance to therapy in B-cell malignancies. Furthermore, we discuss the therapeutic potential of targeting TERT's extratelomeric functions. Unlike telomere-directed approaches, which may require prolonged treatment to achieve effective telomere erosion, inhibiting TERT's extratelomeric functions offers the prospect of rapid tumor-specific effects. This strategy could complement existing chemotherapeutic regimens, providing an innovative and effective approach to managing B-cell malignancies.
端粒酶的重新激活使癌细胞能够维持端粒长度，绕过复制性衰老并实现细胞永生化。除了其在端粒维持中的经典作用外，越来越多的证据表明端粒酶的催化亚基TERT具有不依赖于端粒长度的功能。这些端粒外功能涉及信号通路和转录网络的调节，形成促进癌细胞增殖、抗凋亡和疾病进展的前馈环。本综述探讨了TERT调节关键信号通路（如NF-κB、AKT和MYC）的复杂机制，强调了其在驱动B细胞恶性肿瘤中癌细胞自主生长和抗治疗方面的作用。此外，我们讨论了靶向TERT端粒外功能的治疗潜力。与可能需要长期治疗以实现有效端粒侵蚀的端粒导向方法不同，抑制TERT的端粒外功能有望产生快速的肿瘤特异性效应。该策略可以补充现有的化疗方案，为治疗B细胞恶性肿瘤提供一种创新且有效的方法。
