BIRC5, also known as survivin, is a small protein with a key role in cellular regulation. It belongs to the inhibitor of apoptosis protein (IAP) family, a group of molecules known for controlling programmed cell death. It promotes cell proliferation and prevents apoptosis. This dual role is important in various biological processes within the body. As a regulatory protein, it is central to cell division and survival.
The Role of BIRC5 in Healthy Cells
In healthy cells, BIRC5 functions primarily during cell division (mitosis). It is a component of the chromosome passage protein complex (CPC), which is necessary for proper chromosome alignment and segregation. BIRC5 directs the movement of this complex to different cellular locations, from the inner centromere to the midbody. This organized movement ensures that genetic material is accurately divided between daughter cells.
Beyond mitosis, BIRC5 also prevents programmed cell death (apoptosis). It may counteract natural apoptosis during the G2/M phase of the cell cycle. BIRC5 expression is low or absent in mature tissues, but present in embryonic development and adult stem cells where controlled proliferation is normal. This controlled presence helps maintain cellular homeostasis and proper tissue development.
BIRC5 and Cancer Progression
Overexpression of BIRC5 contributes to cancer development and progression. While largely absent in healthy adult tissues, it is frequently found at high levels in various cancerous tissues. This overexpression allows cancer cells to bypass normal cell death signals, promoting uncontrolled cell proliferation. BIRC5 modulates the cell cycle and inhibits factors in the apoptotic pathway, such as caspase proteins, fostering tumor growth and survival.
Overexpression of BIRC5 is observed in numerous cancer types, including breast cancer, lung adenocarcinoma, kidney renal clear cell carcinoma, gastric cancer, liver cancer, and laryngeal squamous cell carcinoma. For instance, in breast cancer, high BIRC5 expression is linked to poor prognosis and resistance to chemotherapy. In lung adenocarcinoma, BIRC5 upregulation enhances cell proliferation, migration, and invasion, while its reduction suppresses these activities. This protein also contributes to drug resistance in various cancers, making them less responsive to standard chemotherapy and radiation treatments.
Targeting BIRC5 in Treatment
Due to its widespread overexpression in malignancies and limited presence in healthy adult tissues, BIRC5 has emerged as a promising target for cancer therapy. Strategies aim to inhibit BIRC5 or interfere with its expression, restoring apoptosis sensitivity in cancer cells. One approach uses small molecule inhibitors that bind to BIRC5 or disrupt its interactions with partner proteins. For example, YM155 inhibits BIRC5 gene transcription by disrupting Sp1 interaction with the survivin core promoter. Preclinical studies have shown that YM155 can reduce BIRC5 expression and inhibit tumor growth in models of prostate cancer, non-Hodgkin lymphoma, and lung cancer.
Other strategies interfere with BIRC5 expression at the gene or protein level. Gene therapy, using dominant-negative survivin mutants, has been explored to induce apoptosis and repress tumor growth in gastric and breast cancer models. Immunotherapeutic strategies are also under development, using survivin peptide vaccines to elicit a cytotoxic T-cell response against survivin-expressing tumor cells. These vaccines aim to make cancer cells more vulnerable to the body’s immune system, with some advancing through early clinical studies.
BIRC5 as a Biomarker
BIRC5 levels or activity can serve as a valuable biomarker in certain cancers, offering insights into disease prognosis and aiding in diagnosis. Its expression is elevated in tumor tissues across at least 33 cancer types compared to normal tissues. This widespread overexpression makes it a potential diagnostic indicator for various malignancies. For instance, BIRC5 has shown strong diagnostic potential in several cancers, with high accuracy scores in predictive analyses.
Beyond diagnosis, BIRC5 also functions as a prognostic marker, helping to predict patient outcomes. High BIRC5 expression is associated with a poor prognosis across numerous cancers, including lung adenocarcinoma, kidney renal clear cell carcinoma, and laryngeal squamous cell carcinoma. It can indicate more aggressive disease and a shorter overall survival. Furthermore, BIRC5’s potential utility extends to predicting response to therapy and monitoring disease recurrence, as its expression has been linked to chemotherapy resistance in various tumor types.