Signal transducer and activator of transcription 3, known as STAT3, is a protein found within nearly all mammalian cells. It plays a role in cellular processes such as cell growth, cell differentiation, and inflammation response. Normally, STAT3 activation is temporary and tightly controlled in healthy tissues. However, in many cancers, STAT3 becomes persistently active, contributing to tumor development and progression. This dysregulation of STAT3 is a common feature in many tumors.
How STAT3 Contributes to Cancer Growth
When STAT3 is continuously active in cancer cells, it promotes uncontrolled cell proliferation by regulating genes such as Cyclin D1 and cMyc. It also enhances cell survival by suppressing apoptosis, a process of programmed cell death, through the expression of proteins like Bcl2, BclxL, and Mcl1. STAT3 also negatively impacts p53, a protein that inhibits cell proliferation and induces apoptosis.
STAT3 also plays a role in angiogenesis, the formation of new blood vessels essential for tumor growth and spread. It does this by increasing the activity of factors like VEGF (vascular endothelial growth factor) and HIFα. STAT3 aids in metastasis, the spread of cancer cells, by regulating cell migration through molecules like Rho and Rac. It can also upregulate enzymes such as MMP2, MMP7, and MMP9, which help cancer cells invade surrounding tissues.
Beyond direct cellular effects, STAT3 contributes to drug resistance, making cancer treatments less effective. It also helps tumor cells evade the immune system. STAT3 activation in tumor or immune cells can lead to the release of immunosuppressive factors like IL-6 and TNFα, which increase tumor cell survival. This also reduces the activity of natural killer (NK) cells, further protecting cancer cells during circulation.
STAT3’s Complex Role in Cancer
While STAT3 is often associated with promoting tumor growth, its function in cancer is complex and can vary depending on the specific cellular environment and cancer type. In certain situations, STAT3 can exhibit tumor-suppressive functions. This dual nature is influenced by factors such as its activation state and how it interacts with other signaling pathways.
Studies in mouse models of intestinal adenoma have shown that deleting the STAT3 gene enhanced tumor invasion and progression, suggesting a tumor-suppressive role. The STAT3β isoform, a shorter version of the protein, also demonstrates this. In esophageal squamous cell carcinoma, STAT3β has been found to reduce cancer stem cell populations and make cancer cells more sensitive to chemotherapy.
The opposing roles of STAT3 can be influenced by the balance between different STAT3 isoforms, such as STAT3α (the full-length, often oncogenic form) and STAT3β. STAT3β can attenuate the transcriptional activity of STAT3α by forming heterodimers, which impacts how STAT3α binds to DNA and promotes gene expression. Understanding STAT3’s precise role in a given cancer requires considering the specific molecular and cellular context.
Strategies to Target STAT3 in Cancer Treatment
Given STAT3’s involvement in cancer progression, scientists are exploring various approaches to inhibit its activity. One strategy involves small molecule inhibitors, designed to block STAT3 activation or promote its degradation. Many of these inhibitors target the SH2 domain of STAT3, preventing the protein from forming active dimers. Examples include N4 and C188-9, which have shown promise in preclinical studies by inhibiting tumor growth and metastasis.
Other approaches include using peptides or oligonucleotides to interfere with STAT3 signaling. Natural compounds are also being investigated for their ability to modulate STAT3 activity. Beyond direct inhibition, some strategies focus on blocking upstream molecules that activate STAT3, such as antibodies targeting IL-6, a cytokine often implicated in STAT3-driven cancers. Siltuximab, for example, is an IL-6 neutralizing antibody undergoing clinical trials for various cancers.
Despite promising preclinical results, no direct STAT3-targeting drugs have yet been approved for clinical use. Challenges in developing these therapies include ensuring specificity to avoid off-target effects and finding effective ways to deliver the drugs to tumor cells. Ongoing clinical trials are evaluating the safety and effectiveness of STAT3 inhibitors in patients with advanced solid tumors and hematological malignancies. Agents like KT-333 and TTI-101 are currently in Phase 1 trials, showing encouraging signs of biological activity and tolerability.