IL-2 Enhances Cervical Cancer Cells Proliferation and JAK3/STAT5 Phosphorylation at Low Doses, While at High Doses IL-2 Has Opposite Effects

Valle‐Mendiola, Arturo; Weiss‐Steider, Benny; Rocha‐Zavaleta, Leticia; Soto‐Cruz, Isabel

doi:10.3109/07357907.2014.883526

Cited by 30 publications

(36 citation statements)

References 47 publications

(63 reference statements)

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“…Secondly, in addition to STAT3, STAT5 has previously been shown to play an essential role during the productive HPV lifecycle [30,31]. In cervical cancer, STAT5 has been demonstrated to be over-expressed and to correlate with HPV infection [32,33]; however, if STAT5 plays a functional role in cervical cancer pathogenesis is unclear.…”

Section: Stat5 Is a Downstream Mediator Of Jak2 In Hpv+ Cervical Cancmentioning

confidence: 99%

JAK2 Inhibition Impairs Proliferation and Sensitises Cervical Cancer Cells to Cisplatin-Induced Cell Death

Morgan

Macdonald

2019

Cancers

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Persistent infection with high-risk human papillomavirus (HPV) is the underlying cause of ~5% of all human cancers, including the majority of cervical carcinomas and many other ano-genital and oral cancers. A major challenge remains to identify key host targets of HPV and to reveal how they contribute to virus-mediated malignancy. The HPV E6 oncoprotein aberrantly activates the signal transducer and activator of transcription 3 (STAT3) transcription factor and this is achieved by a virus-driven increase in the levels of the pro-inflammatory cytokine interleukin-6 (IL-6) in HPV positive cervical cancers cells. Crucially, STAT3 activity is essential for the proliferation and survival of cervical cancer cells, suggesting that targeting STAT3 may have therapeutic potential. Unfortunately, the development of direct STAT3 inhibitors has been problematic in the clinic due to toxicity issues identified in early stage trials. To overcome this issue, we focused on the protein Janus kinase 2 (JAK2), which phosphorylates STAT3 and is essential for STAT3 activation. Here, we demonstrate that inhibiting JAK2 reduces cell proliferation and induces apoptosis in HPV transformed cervical cancer cells. We further establish that this is due to inhibition of phosphorylation of the JAK2 substrates STAT3 and STAT5. Finally, we demonstrate that the clinically available JAK2 inhibitor Ruxolitinib synergises with cisplatin in inducing apoptosis, highlighting JAK2 as a promising therapeutic target in HPV-driven cancers.

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Section: Stat5 Is a Downstream Mediator Of Jak2 In Hpv+ Cervical Cancmentioning

confidence: 99%

JAK2 Inhibition Impairs Proliferation and Sensitises Cervical Cancer Cells to Cisplatin-Induced Cell Death

Morgan

Macdonald

2019

Cancers

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“…53 This notion is also supported by the STAT3 blockade data demonstrating that STAT3 has an important role in the expansion of Vγ2Vδ2 T cells by IL-23, but not IL-2. [80][81][82] It is interesting to demonstrate that TB can selectively impair IL-23 signaling but spare IL-2 effects on Vγ2Vδ2 T cells. 53,80 Such selective impairing of the IL-23 effect may occur as a result of persistent exposure of Vγ2Vδ2 T cells to phosphoantigen HMBPP or IL-23 during chronic TB infection.…”

Section: Immune Responses Of the Stat3 Pathway And Th17-like Cells Armentioning

confidence: 99%

The crucial roles of Th17-related cytokines/signal pathways in M. tuberculosis infection

2017

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Interleukin-17 (IL-17), IL-21, IL-22 and IL-23 can be grouped as T helper 17 (Th17)-related cytokines because they are either produced by Th17/Th22 cells or involved in their development. Here, we review Th17-related cytokines/Th17-like cells, networks/signals and their roles in immune responses or immunity against Mycobacterium tuberculosis (Mtb) infection. Published studies suggest that Th17-related cytokine pathways may be manipulated by Mtb microorganisms for their survival benefits in primary tuberculosis (TB). In addition, there is evidence that immune responses of the signal transducer and activator of transcription 3 (STAT3) signal pathway and Th17-like T-cell subsets are dysregulated or destroyed in patients with TB. Furthermore, Mtb infection can impact upstream cytokines in the STAT3 pathway of Th17-like responses. Based on these findings, we discuss the need for future studies and the rationale for targeting Th17-related cytokines/signals as a potential adjunctive treatment.

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“…JAK3 is an upstream regulator of STAT5 and STAT6. An accumulating data exercise revealed that inhibition of the JAK3 signaling could reduce cancer progression [37]. It is possible that the suppression of JAK/STAT signaling by gigantol should attenuate CSC in lung cancer.…”

Section: Discussionmentioning

confidence: 99%

Gigantol Targets Cancer Stem Cells and Destabilizes Tumors via the Suppression of the PI3K/AKT and JAK/STAT Pathways in Ectopic Lung Cancer Xenografts

Losuwannarak

Maiuthed

Kitkumthorn

et al. 2019

Cancers

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Lung cancer has long been recognized as an important world heath concern due to its high incidence and death rate. The failure of treatment strategies, as well as the regrowth of the disease driven by cancer stem cells (CSCs) residing in the tumor, lead to the urgent need for a novel CSC-targeting therapy. Here, we utilized proteome alteration analysis and ectopic tumor xenografts to gain insight on how gigantol, a bibenzyl compound from orchid species, could attenuate CSCs and reduce tumor integrity. The proteomics revealed that gigantol affected several functional proteins influencing the properties of CSCs, especially cell proliferation and survival. Importantly, the PI3K/AKT/mTOR and JAK/STAT related pathways were found to be suppressed by gigantol, while the JNK signal was enhanced. The in vivo nude mice model confirmed that pretreatment of the cells with gigantol prior to a tumor becoming established could decrease the cell division and tumor maintenance. The results indicated that gigantol decreased the relative tumor weight with dramatically reduced tumor cell proliferation, as indicated by Ki-67 labeling. Although gigantol only slightly altered the epithelial-to-mesenchymal and angiogenesis statuses, the gigantol-treated group showed a dramatic loss of tumor integrity as compared with the well-grown tumor mass of the untreated control. This study reveals the effects of gigantol on tumor initiation, growth, and maintain in the scope that the cells at the first step of tumor initiation have lesser CSC property than the control untreated cells. This study reveals novel insights into the anti-tumor mechanisms of gigantol focused on CSC targeting and destabilizing tumor integrity via suppression of the PI3K/AKT/mTOR and JAK/STAT pathways. This data supports the potential of gigantol to be further developed as a drug for lung cancer.

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IL-2 Enhances Cervical Cancer Cells Proliferation and JAK3/STAT5 Phosphorylation at Low Doses, While at High Doses IL-2 Has Opposite Effects

Cited by 30 publications

References 47 publications

JAK2 Inhibition Impairs Proliferation and Sensitises Cervical Cancer Cells to Cisplatin-Induced Cell Death

JAK2 Inhibition Impairs Proliferation and Sensitises Cervical Cancer Cells to Cisplatin-Induced Cell Death

The crucial roles of Th17-related cytokines/signal pathways in M. tuberculosis infection

Gigantol Targets Cancer Stem Cells and Destabilizes Tumors via the Suppression of the PI3K/AKT and JAK/STAT Pathways in Ectopic Lung Cancer Xenografts

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