STAT3, the Challenge for Chemotherapeutic and Radiotherapeutic Efficacy

Chemoradiotherapy is one of the most effective and extensively used strategies for cancer treatment. Signal transducer and activator of transcription 3 (STAT3) regulates vital biological processes, such as cell proliferation and cell growth. It is constitutively activated in various cancers and limits the application of chemoradiotherapy. Accumulating evidence suggests that STAT3 regulates resistance to chemotherapy and radiotherapy and thereby impairs therapeutic efficacy by mediating its feedback loop and several target genes. The alternative splicing product STAT3β is often identified as a dominant-negative regulator, but it enhances sensitivity to chemotherapy and offers a new and challenging approach to reverse therapeutic resistance. We focus here on exploring the role of STAT3 in resistance to receptor tyrosine kinase (RTK) inhibitors and radiotherapy, outlining the potential of targeting STAT3 to overcome chemo(radio)resistance for improving clinical outcomes, and evaluating the importance of STAT3β as a potential therapeutic approach to overcomes chemo(radio)resistance. In this review, we discuss some new insights into the effect of STAT3 and its subtype STAT3β on chemoradiotherapy sensitivity, and we explore how these insights influence clinical treatment and drug development for cancer.

Download Full-text

Phospholipase D1 mediates bFGF-induced Bcl-2 expression leading to neurite outgrowth in H19-7 cells

Biochemical Journal ◽

10.1042/bj20110302 ◽

2011 ◽

Vol 441 (1) ◽

pp. 407-416 ◽

Cited By ~ 8

Author(s):

Sung Nyo Yoon ◽

Kang Sik Kim ◽

Ju Hwan Cho ◽

Weina Ma ◽

Hye-Jin Choi ◽

...

Keyword(s):

Neurite Outgrowth ◽

Dominant Negative ◽

Signal Transducer ◽

Downstream Effector ◽

Phospholipase D1 ◽

Protein Kinase Cα ◽

Phosphoinositide 3 Kinase ◽

Interfering Rna ◽

Transcription 3

The purpose of the present study was to investigate the role of PLD (phospholipase D) in bFGF (basic fibroblast growth factor)-induced Bcl-2 expression and to examine whether overexpressed Bcl-2 influences neurite outgrowth in immortalized hippocampal progenitor cells (H19-7 cells). We found that Bcl-2 expression was maximally induced by bFGF within 24 h, and that this effect was reduced by inhibiting PLD1 expression with PLD1 small interfering RNA or by overexpressing DN (dominant-negative)-PLD1, whereas PLD1 overexpression markedly induced Bcl-2 expression. bFGF treatment activated Ras, Src, PI3K (phosphoinositide 3-kinase), PLCγ (phospholipase Cγ) and PKCα (protein kinase Cα). Among these molecules, Src and PKCα were not required for Bcl-2 expression. PLD activity was decreased by Ras, PI3K or PLCγ inhibitor, suggesting that PLD1 activation occurred through Ras, PI3K or PLCγ. We found that Ras was the most upstream molecule among these proteins, followed by the PI3K/PLCγ pathway, indicating that bFGF-induced PLD activation took place through the Ras/PI3K/PLCγ pathway. Furthermore, PLD1 was required for activation of JNK (c-Jun N-terminal kinase), which led to activation of STAT3 (signal transducer and activator of transcription 3) and finally Bcl-2 expression. When Bcl-2 was overexpressed, neurite outgrowth was stimulated along with induction of neurotrophic factors such as brain-derived neurotrophic factor and neurotrophin 4/5. In conclusion, PLD1 acts as a downstream effector of bFGF/Ras/PI3K/PLCγ signalling and regulates Bcl-2 expression through JNK/STAT3, which leads to neurite outgrowth in H19-7 cells.

Download Full-text

A novel role of MNT as a negative regulator of REL and the NF-κB pathway

Oncogenesis ◽

10.1038/s41389-020-00298-4 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Judit Liaño-Pons ◽

M. Carmen Lafita-Navarro ◽

Lorena García-Gaipo ◽

Carlota Colomer ◽

Javier Rodríguez ◽

...

Keyword(s):

Transcription Factor ◽

Target Genes ◽

Transcriptional Regulator ◽

Negative Regulator ◽

Biological Processes ◽

Helix Loop Helix ◽

Bona Fide ◽

E Boxes ◽

Independent Protein

AbstractMNT, a transcription factor of the MXD family, is an important modulator of the oncoprotein MYC. Both MNT and MYC are basic-helix–loop–helix proteins that heterodimerize with MAX in a mutually exclusive manner, and bind to E-boxes within regulatory regions of their target genes. While MYC generally activates transcription, MNT represses it. However, the molecular interactions involving MNT as a transcriptional regulator beyond the binding to MAX remain unexplored. Here we demonstrate a novel MAX-independent protein interaction between MNT and REL, the oncogenic member of the NF-κB family. REL participates in important biological processes and it is altered in a variety of tumors. REL is a transcription factor that remains inactive in the cytoplasm in an inhibitory complex with IκB and translocates to the nucleus when the NF-κB pathway is activated. In the present manuscript, we show that MNT knockdown triggers REL translocation into the nucleus and thus the activation of the NF-κB pathway. Meanwhile, MNT overexpression results in the repression of IκBα, a bona fide REL target. Both MNT and REL bind to the IκBα gene on the first exon, suggesting its regulation as an MNT–REL complex. Altogether our data indicate that MNT acts as a repressor of the NF-κB pathway by two mechanisms: (1) retention of REL in the cytoplasm by MNT interaction, and (2) MNT-driven repression of REL-target genes through an MNT–REL complex. These results widen our knowledge about MNT biological roles and reveal a novel connection between the MYC/MXD and NF-κB pathways, two of the most prominent pathways in cancer.

Download Full-text

A novel role of MNT as a negative regulator of REL and the NF-κB pathway

10.1101/2020.07.21.210989 ◽

2020 ◽

Author(s):

Judit Liaño-Pons ◽

M. Carmen Lafita-Navarro ◽

Carlota Colomer ◽

Lorena García-Gaipo ◽

Javier Rodríguez ◽

...

Keyword(s):

Transcription Factor ◽

Protein Interaction ◽

Target Genes ◽

Negative Regulator ◽

Biological Processes ◽

Helix Loop Helix ◽

Bona Fide ◽

E Boxes ◽

Independent Protein

ABSTRACTMNT, a transcription factor of the MXD family, is an important modulator of the oncoprotein MYC. Both MNT and MYC are basic-helix-loop-helix proteins that heterodimerize with MAX in a mutually exclusive manner, and bind to E-boxes within regulatory regions of their target genes. While MYC generally activates transcription, MNT represses it. However, the molecular interactions involving MNT as a transcriptional regulator beyond the binding to MAX remain unexplored. Here we demonstrate a novel MAX-independent protein interaction between MNT and c-REL (REL), the oncogenic member of the REL/NF-κB family. REL is involved in important biological processes and it is found altered in a variety of tumors. REL is a transcription factor that remains inactive in the cytoplasm in an inhibitory complex with IκB and translocates to the nucleus when the NF-κB pathway is activated. In the present manuscript, we show that MNT knockdown triggers REL translocation into the nucleus and thus the activation of the NF-κB pathway. Meanwhile, MNT overexpression results in the repression of IκBα, a bona-fide REL target. Indeed, both MNT and REL bind to the IκBα gene at a region mapping in the first exon, suggesting its regulation as a MNT-REL complex. Altogether our data indicate that MNT acts as a repressor of the NF-κB pathway by two different mechanisms: 1) retention of REL in the cytoplasm by MNT protein interaction and 2) MNT-driven repression of REL-target genes through a MNT-REL complex. These results widen our knowledge about MNT biological roles and reveal a novel connection between the MYC/MXD and the NF-κB pathways, two of the most prominent pathways involved in cancer.

Download Full-text

Emerging multifaceted roles of BAP1 complexes in biological processes

Cell Death Discovery ◽

10.1038/s41420-021-00406-2 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Aileen Patricia Szczepanski ◽

Lu Wang

Keyword(s):

Transcriptional Repression ◽

Target Genes ◽

Regulatory Mechanisms ◽

Biological Processes ◽

Multiprotein Complex ◽

Downstream Target ◽

Evolutionarily Conserved ◽

Complex Forms ◽

Polycomb Repressive Complex 1

AbstractHistone H2AK119 mono-ubiquitination (H2AK119Ub) is a relatively abundant histone modification, mainly catalyzed by the Polycomb Repressive Complex 1 (PRC1) to regulate Polycomb-mediated transcriptional repression of downstream target genes. Consequently, H2AK119Ub can also be dynamically reversed by the BAP1 complex, an evolutionarily conserved multiprotein complex that functions as a general transcriptional activator. In previous studies, it has been reported that the BAP1 complex consists of important biological roles in development, metabolism, and cancer. However, identifying the BAP1 complex’s regulatory mechanisms remains to be elucidated due to its various complex forms and its ability to target non-histone substrates. In this review, we will summarize recent findings that have contributed to the diverse functional role of the BAP1 complex and further discuss the potential in targeting BAP1 for therapeutic use.

Download Full-text

The Role of Signal Transducer and Activator of Transcription 3 (Stat3) in Stretch Injury to Bladder Smooth Muscle Cells

Journal of Pediatric Urology ◽

10.1016/j.jpurol.2007.01.047 ◽

2007 ◽

Vol 3 ◽

pp. S35

Author(s):

Sarel Halachmi ◽

Karen Aitken ◽

Martha Szybowska ◽

Nesrin Sabha ◽

Shariff Dessouki ◽

...

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Muscle Cells ◽

Signal Transducer ◽

Bladder Smooth Muscle ◽

Stretch Injury ◽

Transcription 3

Download Full-text

Uterine epithelial LIF receptors contribute to implantation chamber formation in blastocyst attachment

Endocrinology ◽

10.1210/endocr/bqab169 ◽

2021 ◽

Author(s):

Yamato Fukui ◽

Yasushi Hirota ◽

Tomoko Saito-Fujita ◽

Shizu Aikawa ◽

Takehiro Hiraoka ◽

...

Keyword(s):

Hormone Receptor ◽

Leukemia Inhibitory Factor ◽

Ovarian Hormones ◽

Signal Transducer ◽

Blastocyst Implantation ◽

Implantation Process ◽

Uterine Glands ◽

Transcription 3

Abstract Recent studies have demonstrated that the formation of an implantation chamber composed of a uterine crypt, an implantation-competent blastocyst, and uterine glands is a critical step in blastocyst implantation in mice. Leukemia inhibitory factor (LIF) activates signal transducer and activator of transcription 3 (STAT3) precursors via uterine LIF receptors (LIFRs), allowing successful blastocyst implantation. Our recent study revealed that the role of epithelial STAT3 is different from that of stromal STAT3. However, both are essential for blastocyst attachment, suggesting the different roles of epithelial and stromal LIFR in blastocyst implantation. However, how epithelial and stromal LIFR regulate the blastocyst implantation process remains unclear. To investigate the roles of LIFR in the uterine epithelium and stroma, we generated Lifr-floxed/lactoferrin (Ltf)-iCre (Lifr eKO) and Lifr-floxed/anti-Mullerian hormone receptor type 2 (Amhr2)-Cre (Lifr sKO) mice with deleted epithelial and stromal LIFR, respectively. Surprisingly, fertility and blastocyst implantation in the Lifr sKO mice were normal despite stromal STAT3 inactivation. In contrast, blastocyst attachment failed, and no implantation chambers were formed in the Lifr eKO mice with epithelial inactivation of STAT3. In addition, normal responsiveness to ovarian hormones was observed in the peri-implantation uteri of the Lifr eKO mice. These results indicate that the epithelial LIFR-STAT3 pathway initiates the formation of implantation chambers, leading to complete blastocyst attachment, and that stromal STAT3 regulates blastocyst attachment without stromal LIFR control. Thus, uterine epithelial LIFR is critical to implantation chamber formation and blastocyst attachment.

Download Full-text

The Role of Signal Transducer and Activator of Transcription 3 (STAT3) and Its Targeted Inhibition in Hematological Malignancies

Cancers ◽

10.3390/cancers10090327 ◽

2018 ◽

Vol 10 (9) ◽

pp. 327 ◽

Cited By ~ 39

Author(s):

Loukik Arora ◽

Alan Kumar ◽

Frank Arfuso ◽

Wee Chng ◽

Gautam Sethi

Keyword(s):

Hematological Malignancies ◽

Signal Transducer ◽

Therapeutic Approaches ◽

Janus Kinases ◽

Constitutive Activation ◽

Targeted Inhibition ◽

Transcription Activators ◽

Apoptotic Effects ◽

Transcription 3

Signal transducer and activator of transcription 3 (STAT3), a member of the STAT protein family, can be phosphorylated by receptor-associated Janus kinases (JAKs) in response to stimulation by cytokines and growth factors. It forms homo- or heterodimers that can translocate to the cell nucleus where they act as transcription activators. Constitutive activation of STAT3 has been found to be associated with initiation and progression of various cancers. It can exert proliferative as well as anti-apoptotic effects. This review focuses on the role of STAT3 in pathogenesis i.e., proliferation, differentiation, migration, and apoptosis of hematological malignancies viz. leukemia, lymphoma and myeloma, and briefly highlights the potential therapeutic approaches developed against STAT3 activation pathway.

Download Full-text

The role of Alx-4 in the establishment of anteroposterior polarity during vertebrate limb development

Development ◽

10.1242/dev.125.22.4417 ◽

1998 ◽

Vol 125 (22) ◽

pp. 4417-4425 ◽

Cited By ~ 6

Author(s):

M. Takahashi ◽

K. Tamura ◽

D. Buscher ◽

H. Masuya ◽

S. Yonei-Tamura ◽

...

Keyword(s):

Negative Feedback ◽

Limb Development ◽

Feedback Loop ◽

Limb Bud ◽

Negative Regulator ◽

Negative Feedback Loop ◽

Vertebrate Limb ◽

Limb Outgrowth ◽

Vertebrate Limb Development

We have determined that Strong's Luxoid (lstJ) [corrected] mice have a 16 bp deletion in the homeobox region of the Alx-4 gene. This deletion, which leads to a frame shift and a truncation of the Alx-4 protein, could cause the polydactyly phenotype observed in lstJ [corrected] mice. We have cloned the chick homologue of Alx-4 and investigated its expression during limb outgrowth. Chick Alx-4 displays an expression pattern complementary to that of shh, a mediator of polarizing activity in the limb bud. Local application of Sonic hedgehog (Shh) and Fibroblast Growth Factor (FGF), in addition to ectodermal apical ridge removal experiments suggest the existence of a negative feedback loop between Alx-4 and Shh during limb outgrowth. Analysis of polydactylous mutants indicate that the interaction between Alx-4 and Shh is independent of Gli3, a negative regulator of Shh in the limb. Our data suggest the existence of a negative feedback loop between Alx-4 and Shh during vertebrate limb outgrowth.

Download Full-text