Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer

Abstract

Transcriptional factors of the NF-kappaB family and STAT3 are ubiquitously expressed and control numerous physiological processes including development, differentiation, immunity, metabolism and cancer. Both NF-kappaB and STAT3 are rapidly activated in response to various stimuli including stresses and cytokines, although they are regulated by entirely different signaling mechanisms. Once activated, NF-kappaB and STAT3 control the expression of anti-apoptotic, pro-proliferative and immune response genes. Some of these genes overlap and require transcriptional cooperation between the two factors. The activation of and interaction between STAT3 and NF-kappaB plays a key role in controlling the dialog between the malignant cell and its microenvironment, especially with inflammatory/immune cells that infiltrate tumors. Quite often, cytokines whose expression is induced in response to NF-kappaB in immune cells of the tumor microenvironment lead to STAT3 activation in both malignant and immune cells. While within malignant and pre-malignant cells STAT3 exerts important oncogenic functions, within inflammatory cells it may also suppress tumor promotion through its anti-inflammatory effects. Other interactions and forms of crosstalk between NF-kappaB and STAT3 include physical interaction between the two, cooperation of these factors at gene promoters/enhancers, the NF-kappaB dependent expression of inhibitors of STAT3 activation and the participation of STAT3 in inflammatory cells in the negative regulation NF-kappaB. Despite these versatile and occasionally antagonistic interactions, NF-kappaB and STAT3 cooperate to promote the development and progression of colon, gastric and liver cancers. In addition to explaining the molecular pathogenesis of cancer, these interactions also offer opportunities for the design of new therapeutic interventions.

Figure 1

Different modes of NF-κB and STAT3 interaction in transcriptional control. A) Activated STAT3 interacts with p65 RelA to recruit the p300 HAT complex to cause RelA, acetylation that prolongs its nuclear retention. This mechanism may mediate STAT3-NF-κB dependent gene transcription. B) STAT3 (either phosphorylated or non-phosphorylated) interacts with p50/NF-κB and/or RelA and together they induce gene transcription through binding to composite sites. C,D) STAT3 and NF-κB do not interact physically, but bind to the same (C) or different (D) promoters, thereby synergistically activating gene expression (C) or acting individually on genes that are either NF-κB- or STAT3-dependent (D).

Figure 2

Signaling pathways that activate NF-κB and STAT3. Different receptors can lead to NF-κB and STAT3. Different receptors can lead to NF-κB activation via IKK and STAT3 activating via JAK1.

Figure 3

Functional interactions between NF-κB and STAT3 in immune cells control the production of pro-inflammatory cytokines that maintain inflammation and stimulate tumor growth by activating NF-κB and STAT3 in cancer cells