Dual Targeting of Y-Box Binding Protein-1 and Akt Inhibits Proliferation and Enhances the Chemosensitivity of Colorectal Cancer Cells

Maier, Eva; Attenberger, Felix; Tiwari, Aadhya; Lettau, Konstanze; Rebholz, Simone; Fehrenbacher, Birgit; Schaller, Martin; Gani, Cihan; Toulany, Mahmoud

doi:10.3390/cancers11040562

Cited by 17 publications

(12 citation statements)

References 55 publications

(82 reference statements)

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“…In this context, hyperactivation of the PI3K/Akt pathway can shift the MAPK/ERK dependency of YB-1 phosphorylation to PI3K/Akt dependency ( Figure 5 B). Therefore, our data uncover an interaction between the two pathways affecting YB-1 activity and, under this condition, dual targeting of PI3K and MEK becomes an efficient approach to block proliferation as depicted in Figure 5 C. According to this model, RSK targeting cannot be used as an effective approach to target YB-1, a conclusion that is also supported by the study in colorectal cancer cells using RSK inhibitor LJI308 [ 52 ].…”

Section: Discussionsupporting

confidence: 53%

“…Independent of the mechanism(s) involved in the activation of the YB-1 in non-TNBC cells, this observation additionally highlights the importance of our findings in targeting the YB-1 pathway not only in TNBC but also in non-TNBC. Additionally, the low level of phosphorylated YB-1 in normal tissue obtained from PT1 ex vivo and previously published data in vitro [ 19 ], as well as in colorectal cancer tissues [ 52 ] suggest that the proposed targeting strategy in our study might spare the normal tissue and thus generate a therapeutic window of opportunity for cancer treatment. The focus of our study was uncovering the signaling pathways involved in YB-1 S102 phosphorylation, but it is known that YB-1 is phosphorylated on other residues as well.…”

Section: Discussionmentioning

confidence: 60%

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Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers

Tiwari

Iida

Kosnopfel

et al. 2020

Cancers

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The multifunctional protein Y-box binding protein-1 (YB-1) regulates all the so far described cancer hallmarks including cell proliferation and survival. The MAPK/ERK and PI3K/Akt pathways are also the major pathways involved in cell growth, proliferation, and survival, and are the frequently hyperactivated pathways in human cancers. A gain of function mutation in KRAS mainly leads to the constitutive activation of the MAPK pathway, while the activation of the PI3K/Akt pathway occurs either through the loss of PTEN or a gain of function mutation of the catalytic subunit alpha of PI3K (PIK3CA). In this study, we investigated the underlying signaling pathway involved in YB-1 phosphorylation at serine 102 (S102) in KRAS(G13D)-mutated triple-negative breast cancer (TNBC) MDA-MB-231 cells versus PIK3CA(H1047R)/PTEN(E307K) mutated TNBC MDA-MB-453 cells. Our data demonstrate that S102 phosphorylation of YB-1 in KRAS-mutated cells is mainly dependent on the MAPK/ERK pathway, while in PIK3CA/PTEN-mutated cells, YB-1 S102 phosphorylation is entirely dependent on the PI3K/Akt pathway. Independent of the individual dominant pathway regulating YB-1 phosphorylation, dual targeting of MEK and PI3K efficiently inhibited YB-1 phosphorylation and blocked cell proliferation. This represents functional crosstalk between the two pathways. Our data obtained from the experiments, applying pharmacological inhibitors and genetic approaches, shows that YB-1 is a key player in cell proliferation, clonogenic activity, and tumor growth of TNBC cells through the MAPK and PI3K pathways. Therefore, dual inhibition of these two pathways or single targeting of YB-1 may be an effective strategy to treat TNBC.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 60%

Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers

Tiwari

Iida

Kosnopfel

et al. 2020

Cancers

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“…Only one mTOR gene has been identified in mammalian cells. mTOR is activated in coordination with other protein complexes [6,7]. It functions as a catalytic subunit of two protein kinase complexes, referred to as mTORC1 and mTORC2 [26].…”

Section: Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

“…By binding to internal ribosomal entry sites (IRES), YB-1 impacts the translation in Snail, Twist, and HIF1alpha and effects the epithelial mesenchymal transition (EMT) [6]. Recent studies in colorectal cancer showed that combining strategies of silencing a dual target, YB-1 through the inhibition of p90 ribosomal S6 kinase (RSK) and Akt, lead to improved sensitivity to standard systemic therapy [7]. This warrants the attempt to connect and understand the impactful molecular mechanisms behind the signaling.…”

Section: Introductionmentioning

confidence: 99%

The Communication between the PI3K/AKT/mTOR Pathway and Y-Box Binding Protein-1 in Gynecological Cancer

Sobočan

Bračič

Knez

et al. 2020

Cancers

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Studies of the mechanistic (mammalian) target of rapamycin inhibitors (mTOR) represent a step towards the targeted treatment of gynecological cancers. It has been shown that women with increased levels of mTOR signaling pathway targets have worse prognosis compared to women with normal mTOR levels. Yet, targeting mTOR alone has led to unsatisfactory outcomes in gynecological cancer. The aim of our review was therefore to provide an overview of the most recent clinical results and basic findings on the interplay of mTOR signaling and cold shock proteins in gynecological malignancies. Due to their oncogenic activity, there are promising data showing that mTOR and Y-box-protein 1 (YB-1) dual targeting improves the inhibition of carcinogenic activity. Although several components differentially expressed in patients with ovarian, endometrial, and cervical cancer of the mTOR were identified, there are only a few investigated downstream actors in gynecological cancer connecting them with YB-1. Our analysis shows that YB-1 is an important player impacting AKT as well as the downstream actors interacting with mTOR such as epidermal growth factor receptor (EGFR), Snail or E-cadherin.

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“…S102 located at YB1 CSD can be phosphorylated by RSK1/2 and AKT ( 23 ). In tumors from cancer patients, YB-1 is highly phosphorylated ( 24 ). Anticancer reagents, ionizing radiation, UV exposure and growth factors also can induce YB-1 phosphorylation ( 23–26 ).…”

Section: Introductionmentioning

confidence: 99%

Structural basis of DNA binding to human YB-1 cold shock domain regulated by phosphorylation

Zhang

Fan

et al. 2020

Nucleic Acids Research

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Human Y-box binding protein 1 (YB-1) is a multifunctional protein and overexpressed in many types of cancer. It specifically recognizes DNA/RNA through a cold shock domain (CSD) and regulates nucleic acid metabolism. The C-terminal extension of CSD and the phosphorylation of S102 are indispensable for YB-1 function. Until now, the roles of the C-terminal extension and phosphorylation in gene transcription and translation are still largely unknown. Here, we solved the structure of human YB-1 CSD with a C-terminal extension sequence (CSDex). The structure reveals that the extension interacts with several residues in the conventional CSD and adopts a rigid structure instead of being disordered. Either deletion of this extension or phosphorylation of S102 destabilizes the protein and results in partial unfolding. Structural characterization of CSDex in complex with a ssDNA heptamer shows that all the seven nucleotides are involved in DNA–protein interactions and the C-terminal extension provides a unique DNA binding site. Our DNA-binding study indicates that CSDex can recognize more DNA sequences than previously thought and the phosphorylation reduces its binding to ssDNA dramatically. Our results suggest that gene transcription and translation can be regulated by changing the affinity of CSDex binding to DNA and RNA through phosphorylation, respectively.

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Dual Targeting of Y-Box Binding Protein-1 and Akt Inhibits Proliferation and Enhances the Chemosensitivity of Colorectal Cancer Cells

Cited by 17 publications

References 55 publications

Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers

Blocking Y-Box Binding Protein-1 through Simultaneous Targeting of PI3K and MAPK in Triple Negative Breast Cancers

The Communication between the PI3K/AKT/mTOR Pathway and Y-Box Binding Protein-1 in Gynecological Cancer

Structural basis of DNA binding to human YB-1 cold shock domain regulated by phosphorylation

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