STAT1-mediated translational control in tumor suppression and antitumor therapies

ABSTRACT

Signal transducer and activator of transcription (STAT1) functions as a tumor suppressor but paradoxically protects tumor cells from death induced by DNA damaging drugs. An important mechanism employed by Stat1 to exert its tumor suppressor and cytoprotective effects involves translation of select mRNAs encoding proteins with either antitumor or prosurvival properties.

KEYWORDS:

• Antitumor therapies
• cell survival
• chemotherapeutic drugs
• gene transcription
• mRNA translation initiation
• protein phosphorylation
• STAT1

Signal transducer and activator of transcription 1 (STAT1) is a key mediator of innate immunity by promoting the antimicrobial and antiproliferative effects of interferons (IFNs).¹ An early intracellular response to IFN treatment is the induction of STAT1 phosphorylation at tyrosine (Y) 701 and serine (S) 727, which is required for the transcriptional induction of a plethora of IFN-stimulated genes (ISGs).¹ However, non-phosphorylated STAT1 maintains its ability to drive the expression of a subset of ISGs encoding proteins involved in cellular resistance to virus infection or DNA damage.^1,2

STAT1 acts as a tumor suppressor by promoting the tumor immunosurveillance properties of IFNs.¹ The antitumor function of STAT1 is also exerted via cell-autonomous mechanisms, best documented by its ability to inhibit the human epidermal growth factor receptor 2 (HER2) and estrogen receptor (ER)-mediated signaling and cell transformation in mouse models of breast cancer.³ In addition, STAT1 acts in a cell autonomous manner to inhibit RAS signaling and lung tumorigenesis via the upregulation of the cyclin dependent kinase (CDK) inhibitor P27^Kip1.⁴ Although inhibition of RAS tumorigenesis depends on phosphorylated STAT1 at Y701,⁴ inhibition of HER2-mediated cell transformation is independent of STAT1 phosphorylation at either Y701 or S727.⁵

The transcriptional function of STAT1 has been implicated in increased resistance of tumor cells to irradiation and genotoxic drug treatments.² Recent findings by our group revealed a novel function of STAT1 in regulation of the initiation of messenger RNA translation.⁶ Specifically, STAT1 promotes the transcription of PIK3CG, which encodes the catalytic γ subunit of phosphoinositide 3-kinase (PI3K) class IB and contributes to the induction of the PI3K-Akt (also known as protein kinase B or PKB) pathway in response to mitogenic stimuli.⁶ STAT1 also mediates the transcriptional upregulation of 4EBP1, which encodes the translation initiation factor eIF4E-binding protein 1 (4EBP1) and leads to inhibition of cap-dependent mRNA translation and cell proliferation.⁶ Stimulation of PI3K-AKT/PKB signaling by STAT1 results in activation of the mammalian target of rapamycin complex 1 (MTORC1) and ribosomal S6 kinase (S6K), which in turn mediates the proteasomal degradation of programmed cell death protein 4 (PDCD4).⁶ PDCD4 is a tumor suppressor protein that interacts with and impairs the RNA helicase activity of the eukaryotic translation initiation factor 4A (EIF4A) leading to inhibition of mRNA translation initiation.⁷ The ability of STAT1 to downregulate PDCD4 and at the same time upregulate 4EBP1 establishes conditions in cells that favor the cap-independent translation of select mRNAs encoding P27^Kip1, X-linked inhibitor of apoptosis (XIAP), and B-cell lymphoma X L (BCL-XL) proteins (Fig. 1).⁶ Increased P27^Kip1 results in the inhibition of cell proliferation whereas upregulation of XIAP and BCL-XL protects tumor cells from death caused by genotoxic drugs such as doxorubicin.⁶ Thus, through the translational upregulation of select mRNAs STAT1 fulfills 2 distinct functions leading to inhibition of tumor growth and increased survival in the presence of DNA damaging drugs (Fig. 1).⁶

Figure 1. Schematic model of the cell-autonomous translational effects of STAT1 on tumors. Upregulation of the eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) contributes to the cell autonomous antitumor properties of the signal transducer and activator of transcription 1 (STAT1) through inhibition of general protein synthesis and cell proliferation. STAT1 exerts a prosurvival function, which depends on increased phosphoinositide 3-kinase (PI3K) signaling and programmed cell death protein 4 (PDCD4) degradation as a result of AKT/protein kinase B (PKB) and ribosomal S6 kinase (S6K)-mediated phosphorylation (not shown). Downregulation of PDCD4 results in increased eukaryotic translation initiation factor 4A (EIF4A) activity, which favors the cap-independent translation of the cyclin-dependent kinase (CDK) inhibitor P27^Kip1, X-linked inhibitor of apoptosis (XIAP), and B-cell lymphoma X L (BCL-XL) protein. Increased P27^Kip1 contributes to tumor suppression whereas increased BCL-XL and XIAP protects tumor cells from DNA damaging drugs.

An important question is whether the effects of STAT1 on mRNA translation could be exploited for the design of effective anticancer therapies. Because STAT1 exerts both antiproliferative and prosurvival functions in tumors, the answer is not obvious. The antitumor function of STAT1 depends on both immunoregulatory and cell-autonomous mechanisms. On the other hand, the prosurvival function requires the cell-autonomous effects of STAT1 on gene transcription and translation inasmuch as the role of the immune regulatory effects of STAT1 on tumor survival is not known. Doxorubicin and other anthracyclines cause immunogenic tumor death, which requires the activation of select immune effector cells by the dying tumor cells under conditions of immunosuppression.⁸ STAT1 renders tumor cells resistant to doxorubicin, raising the hypothesis that its downregulation in tumors may facilitate the induction of immunogenic death by doxorubicin and other DNA damaging drugs. In this respect, fludarabine, a drug that selectively downregulates STAT1, has been shown to induce lymphopenia and contribute to the induction of immunogenic death in combination therapies with cyclophosphamide.⁸ However, some studies have indicated that the absence of STAT1 promotes the expansion of T regulatory cells,⁹ an effect that could limit the efficacy of therapies inducing immunogenic death.⁸ Thus, targeting STAT1 expression in tumors by pharmacologic means may elicit ambivalent effects by disarming prosurvival pathways within the tumors but, at the same time, weakening the antitumor effects of the immune cells in the tumor bed. Thus, it is important to decipher the role of STAT1 in the cell autonomous and immune regulatory responses of tumors to therapeutic drugs and determine which of the 2 components prevails in antitumor treatments under conditions of impaired STAT1 expression.

The ability of STAT1 to downregulate PDCD4 may be the “Achilles heel” of tumors with elevated STAT1 such as glioblastomas and mesotheliomas. Specifically, PDCD4 downregulation by STAT1 plays an important role in the cap-independent translation of mRNAs encoding the antiapoptotic BCL-XL and XIAP as a result of increased EIF4A activity.⁶ As such, restoration of PDCD4 function by the newly developed drug inhibitors of EIF4A translational activity may hold promise for the implementation of effective anticancer therapies by impairing the translational effects of STAT1.¹⁰ Such an approach may be of clinical benefit if the pharmacologic eIF4A inhibitors exhibit an increased specificity for the cell-autonomous and prosurvival functions of STAT1 with minimal effects on its immunoregulatory functions, which are required for mounting an effective antitumor response.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Funding

The work was supported by funds from the Cancer Research Society Inc., the Marjorie Sheridan Innovation grant of the Canadian Cancer Society (CCSRI #701631), and Quebec Breast Cancer Foundation (QBCF) to AEK.