The RAS signal transduction pathway and its role in radiation sensitivity

McKenna, W. Gillies; Muschel, Ruth J.; Gupta, Anjali; Hahn, Stephen M.; Bernhard, Eric J.

doi:10.1038/sj.onc.1206699

Cited by 123 publications

(36 citation statements)

References 67 publications

(64 reference statements)

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“…Activation of RAS, RAF-1, mitogen-activating protein kinase (MAPK), p38, and PI3K pathways has been associated with radioresistance 92 and could account for hypoxia-induced survival advantages via direct inhibition of apoptosis or enhanced HIF-1α activity. 93,94 Breast cancer, chronic lymphoid leukaemia, and myeloma cells with aberrant notch 1 signalling become chemoresistant upon inhibition of the p53 pathway by the mTOR-dependent PI3K/AKT/PKB pathway. 95,96 Silencing of notch 1 has been shown to promote docetaxel-induced cell growth inhibition, apoptosis, and cell cycle arrest in PC3 cells, 97 whereas expression of the notch 2 homologue protein has been associated with radiosensitivity in patients with locally advanced adenocarcinoma of the rectum.…”

Section: Treatment Resistancementioning

confidence: 99%

Hypoxia, notch signalling, and prostate cancer

et al. 2013

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The notch signalling pathway is involved in differentiation, proliferation, angiogenesis, vascular remodelling, and apoptosis. Deregulated expression of notch receptors, ligands, and targets is observed in many solid tumours, including prostate cancer. Hypoxia is a common feature of prostate tumours, leading to increased gene instability, reduced treatment response, and increased tumour aggressiveness. The notch signalling pathway is known to regulate vascular cell fate and is responsive to hypoxia-inducible factors. Evidence to date suggests similar, therapeutically exploitable, behaviour of notch-activated and hypoxic prostate cancer cells.

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Section: Treatment Resistancementioning

confidence: 99%

Hypoxia, notch signalling, and prostate cancer

et al. 2013

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“…AKT is a serine-threonine kinase; upon phosphorylation at T308 and S473, AKT activates several target proteins that are involved in tumor cell proliferation, apoptosis, and the cell cycle [41, 42]. Deregulation of the PI3K/AKT/mTOR pathway is highly involved in lung carcinogenesis, as this pathway is extensively interconnected with other oncogenic signaling [41, 43–45]. Therefore, HMGA1, a regulator of the PI3K/AKT/mTOR pathway, is a potential target for lung cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

IL-24 modulates the high mobility group (HMG) A1/miR222 /AKT signaling in lung cancer cells

et al. 2016

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Interleukin (IL)-24, a novel tumor suppressor/cytokine exhibits antitumor activity against a broad-spectrum of human cancer cells. In a recent study, we showed that IL-24 inhibited AKT in lung cancer cells. However, the molecular mechanism of AKT inhibition by IL-24 remains elusive.The high mobility group (HMG) A1 a member of the non-histone chromosomal proteins and commonly referred to as architectural transcription factor, regulates transcription of various genes involved in cell growth and survival. Overexpression of HMGA1 has been shown to be associated with tumor progression and metastasis in several cancers, including human lung cancer. A recent study demonstrated that HMGA1 activates AKT function by reducing the activity of the protein phosphatase, phosphatase 2A subunit B (PPP2R2A) via the oncogenic micro (mi) RNA-222. Based on this report we hypothesized that IL-24-mediated AKT inhibition involved the HMGA1/miR-222 axis.To test our hypothesis, in the present study we used a H1299 lung cancer cell line that expressed exogenous human IL-24 when induced with doxycycline (DOX). Induction of IL-24 expression in the tumor cells markedly reduced HMGA1 mRNA and protein levels. Using a mechanistic approach, we found that IL-24 reduced miR-222-3p and -5p levels, as determined by qRT-PCR. Associated with HMGA1 and miR-222 inhibition was a marked increase in PPP2R2A, with a concomitant decrease in phosphorylated AKTT308/S473 expression. SiRNA-mediated knockdown of HMGA1 in combination with IL-24 significantly reduced AKT T308/S473 protein expression and greatly reduced cell migration and invasion compared with individual treatments. Further combination of IL-24 and a miR-222-3p inhibitor significantly increased PPP2R2A expression.Our results demonstrate for the first time that IL-24 inhibits AKT via regulating the HMGA1/miR-222 signaling node in human lung cancer cells and acts as an effective tumor suppressor. Thus, a therapy combining IL-24 with HMGA1 siRNA or miR-222-3p inhibitor should present effective treatment of lung cancer.

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“…Second, radiation may reduce the high pressure of tumor cells which serves as an obstacle for virus replication and spread in vivo . Third, Ras mutation is one of the driver mutations for melanoma and is associated with radio-resistance [141-143]. However, reovirus, VSV and HSV have been demonstrated to preferentially target the Ras mutated melanoma cells and induce apoptosis [88, 89].…”

Section: Melanoma Therapies and Emergence Of Oncolytic Virotherapymentioning

confidence: 99%

Targeting Melanoma with Cancer-Killing Viruses

Zhang¹,

Suryawanshi²,

Woyczesczyk³

et al. 2017

TOVJ

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Melanoma is the deadliest skin cancer with ever-increasing incidence. Despite the development in diagnostics and therapies, metastatic melanoma is still associated with significant morbidity and mortality. Oncolytic viruses (OVs) represent a class of novel therapeutic agents for cancer by possessing two closely related properties for tumor reduction: virus-induced lysis of tumor cells and induction of host anti-tumor immune responses. A variety of viruses, either in “natural” or in genetically modified forms, have exhibited a remarkable therapeutic efficacy in regressing melanoma in experimental and/or clinical studies. This review provides a comprehensive summary of the molecular and cellular mechanisms of action of these viruses, which involve manipulating and targeting the abnormalities of melanoma, and can be categorized as enhancing viral tropism, targeting the tumor microenvironment and increasing the innate and adaptive antitumor responses. Additionally, this review describes the “biomarkers” and deregulated pathways of melanoma that are responsible for melanoma initiation, progression and metastasis. Advances in understanding these abnormalities of melanoma have resulted in effective targeted and immuno-therapies, and could potentially be applied for engineering OVs with enhanced oncolytic activity in future.

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The RAS signal transduction pathway and its role in radiation sensitivity

Cited by 123 publications

References 67 publications

Hypoxia, notch signalling, and prostate cancer

Hypoxia, notch signalling, and prostate cancer

IL-24 modulates the high mobility group (HMG) A1/miR222 /AKT signaling in lung cancer cells

Targeting Melanoma with Cancer-Killing Viruses

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