FoxO-1 contributes to the efficacy of the combination of the XPO1 inhibitor selinexor and cisplatin in ovarian carcinoma preclinical models

Corno, Cristina; Stucchi, Simone; Cesare, Michelandrea De; Carenini, Nives; Stamatakos, Serena; Ciusani, Emilio; Minoli, Lucia; Scanziani, Eugenio; Argueta, Christian; Landesman, Yosef; Zaffaroni, Nadia; Gatti, Laura; Perego, Paola

doi:10.1016/j.bcp.2017.11.009

Cited by 36 publications

(34 citation statements)

References 29 publications

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“…Among the small molecules that inhibit exportin-1 function, selinexor (KPT-330) is under clinical trials for most cancer types, including leukemia, and lung, prostate, gastric, breast, ovarian, and cervical cancers [32]. Although the synergistic effects of the combination of selinexor and cisplatin have been evaluated in the ovarian cancer preclinical models [33], but in cervical cancer, selinexor is only been reported to be effective as a single-agent [34]. Herein, we suggest for the first time that exportin-1 inhibitor can be used in combination with cisplatin to ameliorate cervical cancer progression.…”

Section: Discussionmentioning

confidence: 99%

HP1γ Sensitizes Cervical Cancer Cells to Cisplatin through the Suppression of UBE2L3

Kim

Yoo

et al. 2020

IJMS

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Cisplatin is the most frequently used agent for chemotherapy against cervical cancer. However, recurrent use of cisplatin induces resistance, representing a major hurdle in the treatment of cervical cancer. Our previous study revealed that HP1γ suppresses UBE2L3, an E2 ubiquitin conjugating enzyme, thereby enhancing the stability of tumor suppressor p53 specifically in cervical cancer cells. As a follow-up study of our previous findings, here we have identified that the pharmacological substances, leptomycin B and doxorubicin, can improve the sensitivity of cervical cancer cells to cisplatin inducing HP1γ-mediated elevation of p53. Leptomycin B, which inhibits the nuclear export of HP1γ, increased cisplatin-dependent apoptosis induction by promoting the activation of p53 signaling. We also found that doxorubicin, which induces the DNA damage response, promotes HP1γ-mediated silencing of UBE2L3 and increases p53 stability. These effects resulted from the nuclear translocation and binding of HP1γ on the UBE2L3 promoter. Doxorubicin sensitized the cisplatin-resistant cervical cancer cells, enhancing their p53 levels and rate of apoptosis when administered together with cisplatin. Our findings reveal a therapeutic strategy to target a specific molecular pathway that contributes to p53 degradation for the treatment of patients with cervical cancer, particularly with cisplatin resistance.

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Section: Discussionmentioning

confidence: 99%

HP1γ Sensitizes Cervical Cancer Cells to Cisplatin through the Suppression of UBE2L3

Kim

Yoo

et al. 2020

IJMS

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“…The early pre-clinical studies in ovarian cancer cells were instrumental in furthering the understanding of CRM1 inhibitors (21). Ovarian cancer cells demonstrated sensit iv it y to t he ef fects of selinexor alone and in combination with cisplatin (42). The growth inhibition effect was thought to be from FOXO1 targeting, which has been implicated in platinum-resistant disease.…”

Section: Gynecologic Cancermentioning

confidence: 99%

The past, present, and future of CRM1/XPO1 inhibitors

Wang¹,

Liu²

2019

Stem Cell Investig

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Therapies targeted at inhibiting nucleo-cytoplasmic transport have found broad applications in the field of oncology. Chromosome region maintenance 1 (CRM1), better known as exportin 1 (XPO1), is the protein transporter responsible for the nucleo-cytoplasmic shuttling of most of the tumor suppressor proteins (TSP) and growth regulatory factors. XPO1 is also upregulated in many malignancies and associated with a poor prognosis. Its inhibition has been a target of therapy, and hence, the selective inhibitors of nuclear transport (SINE) compounds were developed as a novel class of anti-cancer agents. The most well-known SINE agent is selinexor (KPT-330) and has been widely tested in phase I and II clinical trials in both solid tumors and hematologic malignancies. This review discusses how dysregulation of XPO1 promotes tumorigenesis, the historical considerations in the development of SINE compounds, and their role in current clinical therapies.

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“…In ovarian carcinoma preclinical models, FoxO1 contributes to the efficacy of the combination of cisplatin and selinexor, a selective inhibitor of the nuclear export receptor (XPO1)/Chromosome Region Maintenance-1 (CRM1) [63], because a stronger synergistic interaction was observed in cells expressing FoxO1 than in cells in which FoxO1 was down-regulated. XPO1 participates in the nuclear export of tumor suppressor and cell cycle regulating proteins, including FoxOs.…”

Section: Foxos and Drug Responsementioning

confidence: 99%

Role of FoxO Proteins in Cellular Response to Antitumor Agents

Beretta

Corno

Zaffaroni

et al. 2019

Cancers

Self Cite

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FoxO proteins (FoxOs) are transcription factors with a common DNA binding domain that confers selectivity for DNA interaction. In human cells, four proteins (FoxO1, FoxO3, FoxO4 and FoxO6), with redundant activity, exhibit mainly a positive effect on genes involved in cell cycle, apoptosis regulation and drug resistance. Thus, FoxOs can affect cell response to antitumor agent treatment. Their transcriptional activity depends on post-translational modifications, including phosphorylation, acetylation, and mono/poly-ubiquitination. Additionally, alterations in microRNA network impact on FoxO transcripts and in turn on FoxO levels. Reduced expression of FoxO1 has been associated with resistance to conventional agents (e.g., cisplatin) and with reduced efficacy of drug combinations in ovarian carcinoma cells. FoxO3 has been shown as a mediator of cisplatin toxicity in colorectal cancer. A requirement for FoxO3-induced apoptosis has been reported in cells exposed to targeted agents (e.g., gefitinib). Recently, the possibility to interfere with FoxO1 localization has been proposed as a valuable approach to improve cell sensitivity to cisplatin, because nuclear retention of FoxO1 may favor the induction of pro-apoptotic genes. This review focuses on the role of FoxOs in drug treatment response in tumor cells and discusses the impact of the expression of these transcription factors on drug resistance/sensitivity.

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FoxO-1 contributes to the efficacy of the combination of the XPO1 inhibitor selinexor and cisplatin in ovarian carcinoma preclinical models

Cited by 36 publications

References 29 publications

HP1γ Sensitizes Cervical Cancer Cells to Cisplatin through the Suppression of UBE2L3

HP1γ Sensitizes Cervical Cancer Cells to Cisplatin through the Suppression of UBE2L3

The past, present, and future of CRM1/XPO1 inhibitors

Role of FoxO Proteins in Cellular Response to Antitumor Agents

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