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Autophagy Modulation in Human Thyroid Cancer Cells following Aloperine Treatment.

ABSTRACT: Aloperine, an alkaloid isolated from Sophora alopecuroides, exhibits multiple pharmacological activities including anti-inflammatory, antioxidant, antiallergic, antinociceptive, antipathogenic, and antitumor effects. Furthermore, it exerts protective effects against renal and neuronal injuries. Several studies have reported antitumor effects of aloperine against various human cancers, including multiple myeloma; colon, breast, and prostate cancers; and osteosarcoma. Cell cycle arrest, apoptosis induction, and tumorigenesis suppression have been demonstrated following aloperine treatment. In a previous study, we demonstrated antitumor effects of aloperine on human thyroid cancer cells through anti-tumorigenesis and caspase-dependent apoptosis induction via the Akt signaling pathway. In the present study, we demonstrated the modulation of the autophagy mechanism following the incubation of multidrug-resistant papillary and anaplastic human thyroid cancer cells with aloperine; we also illustrate the underlying mechanisms, including AMPK, Erk, JNK, p38, and Akt signaling pathways. Further investigation revealed the involvement of the Akt signaling pathway in aloperine-modulated autophagy in human thyroid cancer cells. These results indicate a previously unappreciated function of aloperine in autophagy modulation in human thyroid cancer cells.

SUBMITTER: Yu HI

PROVIDER: S-EPMC6862658 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Autophagy Modulation in Human Thyroid Cancer Cells following Aloperine Treatment.

Yu Hui-I HI Shen Hui-Ching HC Chen Shu-Hsin SH Lim Yun-Ping YP Chuang Hsiang-Hsun HH Tai Tsai-Sung TS Kung Fang-Ping FP Lu Chieh-Hsiang CH Hou Chia-Yi CY Lee Ying-Ray YR

International journal of molecular sciences 20191025 21

Aloperine, an alkaloid isolated from <i>Sophora</i> <i>alopecuroides</i>, exhibits multiple pharmacological activities including anti-inflammatory, antioxidant, antiallergic, antinociceptive, antipathogenic, and antitumor effects. Furthermore, it exerts protective effects against renal and neuronal injuries. Several studies have reported antitumor effects of aloperine against various human cancers, including multiple myeloma; colon, breast, and prostate cancers; and osteosarcoma. Cell cycle arre ...[more]

PMID: 31731481

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Project description:BackgroundSodium/iodide symporter (NIS)-mediated iodide uptake plays an important physiological role in regulating thyroid gland function, as well as in diagnosing and treating Graves' disease and thyroid cancer. High-mobility group box 1 (HMGB1), a highly conserved nuclear protein, is a positive regulator of autophagy conferring resistance to chemotherapy, radiotherapy and immunotherapy in cancer cells. Here the authors intended to identify the role of HMGB1 in Hank's balanced salt solution (HBSS)-induced autophagy, explore NIS protein degradation through a autophagy-lysosome pathway in thyroid cancer cells and elucidate the possible molecular mechanisms.MethodsImmunohistochemical staining and reverse transcription-polymerase chain reaction (RT-PCR) were performed for detecting the expression of HMGB1 in different tissues. HMGB1 was knocked down by lentiviral transfection in FTC-133/TPC-1 cells. Autophagic markers LC3-II, p62, Beclin1 and autophagosomal formation were employed for evaluating HMGB1-mediated autophagy in HBSS-treated cells by Western blot, immunofluorescence and electron microscopy. Western blot, quantitative RT-PCR and gamma counter analysis were performed for detecting NIS expression and iodide uptake in HMGB1-knockdown cells after different treatments. The reactive oxygen species (ROS) level, ROS-mediated LC3-II expression and HMGB1 cytosolic translocation were detected by fluorospectrophotometer, flow cytometry, Western blot and immunofluorescence. HMGB1-mediated AMPK, mTOR and p70S6K phosphorylation (p-AMPK, p-mTOR & p-p70S6K) were detected by Western blot. Furthermore, a nude murine model with transplanted tumor was employed for examining the effect of HMGB1-mediated autophagy on imaging and biodistribution of 99mTcO4-. NIS, Beclin1, p-AMPK and p-mTOR were detected by immunohistochemical staining and Western blot in transplanted tumor samples.ResultsHMGB1 was a critical regulator of autophagy-mediated NIS degradation in HBSS-treated FTC-133/TPC-1 cells. And HMGB1 up-regulation was rather prevalent in thyroid cancer tissues and closely correlated with worse overall lymph node metastasis and clinical stage. HMGB1-knockdown dramatically suppressed autophagy, NIS degradation and boosted iodide uptake in HBSS-treated cells. Moreover, HBSS enhanced ROS-sustained autophagy and promoted the cytosolic translocation of HMGB1. A knockdown of HMGB1 suppressed LC3-II conversion and NIS degradation via an AMPK/mTOR-dependent signal pathway through a regulation of ROS generation, rather than ATP. Furthermore, these data were further supported by our in vivo experiment of xenografts formed by HMGB1 knockdown cells reverting the uptake of 99mTcO4- as compared with control shRNA-transfected cells in hunger group.ConclusionsActing as a critical regulator of autophagy-mediated NIS degradation via ROS/AMPK/mTOR pathway, HMGB1is a potential intervention target of radioiodine therapy in thyroid cancer.

Project description:Purpose: In an HIV cure setting, Vorinostat may provide the “shock” capable of flushing HIV out of the persistent reservoir, while antiretroviral therapy is used to prevent new infections. However, this drug may modulate the expression of human endogenous retroviruses (HERVs). This study demonstrates significant modulation of HERVs and suggests that they should be considered as off-target effects of this drug treatment. Methods: Peripheral blood mononuclear cells were collected from 4 healthy donors. Naive CD4 T cells were isolated and utilized to assess HERV dysregulation after treatment with Vorinostat. Cells were collected for study and exposed to a dose of Vorinostat (10uM dose over a 24 hour period). After this, RNA was extracted from cells and their untreated paired counterparts for deep sequencing by Expression Analysis. Sequence reads that passed quality filters were mapped to the HERVd reference database using Bowtie and counted using HTSeq. Any HERV which did not achieve at least 1 count per million mapped and counted reads in at least 4 samples was discarded. Differential expression was performed upon the filtered dataset with edgeR and using TMM normalization. Results: Using an custom built data analysis pipeline, ~100 million reads per sample were mapped to the HERVd reference database and identified 10784 distinct dysregulated elements Bowtie/HTSeq workflow. Differential expression analysis was performed between vorinostat treated and untreated conditions which demonstrated 2102 dysregulated HERV elements with 1007 downregulated and 1095 upregulated (FDR < 0.05) with EdgeR. Results were further subset with a log2FC ± 3 which resulted in 451 upregulated and 363 downregulated HERV elements from 81 and 82 distinct families respectively. HERV elements from the LTR12 family were by far the most dramatically upregulated in family frequency and fold change magnitude. Further confirmation with droplet digital PCR confirmed upregulation of LTR12 elements and demonstrated an exponential dose response curve with HERV expression found at even moderate doses (334nM) of vorinostat treatment. Conclusions: This study represents the first detailed analysis of HERV dysregulation following vorinostat treatment using the untargeted approach of total RNA-Seq. These results demonstrate that vorinostat dysregulates multiple HERV families with a propensity to upregulate members of the LTR12 HERV family. This study also provides a methodology to analyze HERV dysregulation in future treatments with vorinostat or other drugs by providing a mechanism to choose primer and probe sets which will properly represent HERV dysregulation as expression across an HERV is not uniform or continuous. Finally, this work suggests that HERV dysregulation by vorinostat treatment should be considered an off-target effect of this drug and HERV elements, such as LTR12, should be monitored as biomarkers during shock and kill clinical trials with HDAC inhibitors and that trial subjects should be screened to explore further HIV:HERV interactions.

Dataset Information

Autophagy Modulation in Human Thyroid Cancer Cells following Aloperine Treatment.

Publications

Autophagy Modulation in Human Thyroid Cancer Cells following Aloperine Treatment.

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