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High mobility group A1 protein expression reduces the sensitivity of colon and thyroid cancer cells to antineoplastic drugs.

ABSTRACT: Development of resistance to conventional drugs and novel biological agents often impair long-term chemotherapy. HMGA gene overexpression is often associated with antineoplastic drug resistance and reduced survival. Inhibition of HMGA expression in thyroid cancer cells reduces levels of ATM protein, the main cellular sensor of DNA damage, and enhances cellular sensitivity to DNA-damaging agents. HMGA1 overexpression promotes chemoresistance to gemcitabine in pancreatic adenocarcinoma cells through an Akt-dependent mechanism.To elucidate the role of HMGA1 proteins in chemoresistance we analyzed resistance to conventional drugs and targeted therapies of human colon carcinoma cells (GEO) that are sensitive to the epidermal growth factor receptor inhibitor cetuximab, and express minimal levels of HMGA1 and cetuximab-resistant (GEO CR) cells expressing high HMGA1 protein levels.GEO CR cells were less sensitive than GEO cells to cetuximab and 5-fluorouracil. GEO CR cells silenced for HMGA1 expression were more susceptible than empty vector-transfected cells to the drugs' cytotoxicity. Similar results were obtained with anaplastic thyroid carcinoma cells expressing or not HMGA1 proteins, treated with doxorubicin or the HDAC inhibitor LBH589. Finally, HMGA1 overexpression promoted the DNA-damage response and stimulated Akt phosphorylation and prosurvival signaling.Our findings suggest that the blockage of HMGA1 expression is a promising approach to enhance cancer cell chemosensitivity, since it could increase the sensitivity of cancer cells to antineoplastic drugs by inhibiting the survival signal and DNA damage repair pathways.

SUBMITTER: D'Angelo D

PROVIDER: S-EPMC4247615 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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High mobility group A1 protein expression reduces the sensitivity of colon and thyroid cancer cells to antineoplastic drugs.

D'Angelo Daniela D Mussnich Paula P Rosa Roberta R Bianco Roberto R Tortora Giampaolo G Fusco Alfredo A

BMC cancer 20141120

<h4>Background</h4>Development of resistance to conventional drugs and novel biological agents often impair long-term chemotherapy. HMGA gene overexpression is often associated with antineoplastic drug resistance and reduced survival. Inhibition of HMGA expression in thyroid cancer cells reduces levels of ATM protein, the main cellular sensor of DNA damage, and enhances cellular sensitivity to DNA-damaging agents. HMGA1 overexpression promotes chemoresistance to gemcitabine in pancreatic adenoca ...[more]

PMID: 25409711

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Project description:High Mobility Group A1 (HMGA1) is an architectural chromatin protein whose overexpression is a feature of malignant neoplasias with a causal role in cancer initiation and progression. HMGA1 promotes tumor growth by several mechanisms, including increase of cell proliferation and survival, impairment of DNA repair and induction of chromosome instability. Autophagy is a self-degradative process that, by providing energy sources and removing damaged organelles and misfolded proteins, allows cell survival under stress conditions. On the other hand, hyper-activated autophagy can lead to non-apoptotic programmed cell death. Autophagy deregulation is a common feature of cancer cells in which has a complex role, showing either an oncogenic or tumor suppressor activity, depending on cellular context and tumor stage. Here, we report that depletion of HMGA1 perturbs autophagy by different mechanisms. HMGA1-knockdown increases autophagosome formation by constraining the activity of the mTOR pathway, a major regulator of autophagy, and transcriptionally upregulating the autophagy-initiating kinase Unc-51-like kinase 1 (ULK1). Consistently, functional experiments demonstrate that HMGA1 binds ULK1 promoter region and negatively regulates its transcription. On the other hand, the increase in autophagosomes is not associated to a proportionate increase in their maturation. Overall, the effects of HMGA1 depletion on autophagy are associated to a decrease in cell proliferation and ultimately impact on cancer cells viability. Importantly, silencing of ULK1 prevents the effects of HMGA1-knockdown on cellular proliferation, viability and autophagic activity, highlighting how these effects are, at least in part, mediated by ULK1. Interestingly, this phenomenon is not restricted to skin cancer cells, as similar results have been observed also in HeLa cells silenced for HMGA1. Taken together, these results clearly indicate HMGA1 as a key regulator of the autophagic pathway in cancer cells, thus suggesting a novel mechanism through which HMGA1 can contribute to cancer progression.

Project description: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.

Dataset Information

High mobility group A1 protein expression reduces the sensitivity of colon and thyroid cancer cells to antineoplastic drugs.

Publications

High mobility group A1 protein expression reduces the sensitivity of colon and thyroid cancer cells to antineoplastic drugs.

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