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Autophagy and chemoresistance

Feng Lin, Li Gao, Zhenyu Su, Xiaofang Cao, Yuanbo Zhan, Ying Li, Bin Zhang
Oral squamous cell carcinoma (OSCC), one of the 10 most common types of neoplasms in the US, constitutes ~90% of all cases of oral malignancies. Chemoresistance and metastasis are difficult to avoid during the course of treatment, leading to a poor prognosis and a high mortality rate for patients with OSCC. Autophagy, a critical conserved cellular process, has been reported to be highly associated with the regulation of chemoresistance and metastasis of cancer cells. The present study investigated the role of karyopherin α2 (KPNA2), a member of the importin α family, which may serve an important role in p53 nucleocytoplasmic transport in the process of OSCC autophagy...
May 17, 2018: Oncology Reports
Y X Zhao, Z F Sun
Head and neck squamous cell carcinoma (HNSCC) is an aggressive neoplasm with the properties of local recurrence and distant metastasis. Currently, cisplatin-based chemotherapy or concurrent radiochemotherapy is still the first choice or the treatment of advanced HNSCC. However, chemoresistance greatly limited the effectiveness of chemotherapy. Therefore, illustrating the mechanisms of chemoresistance is very important for the treatment of HNSCC. In this article, we summarize the molecular mechanisms of chemoresitance in HNSCC from the perspective of drug efflux, apoptosis, DNA damage and repair, epithelial mesenchymal transition and autophagy...
June 5, 2017: Journal of Clinical Otorhinolaryngology, Head, and Neck Surgery
Oxana Ryabaya, Anastasia Prokofieva, Dmitry Khochenkov, Ivan Abramov, Alexander Zasedatelev, Evgenia Stepanova
The incidence of malignant melanoma is increasing. The discovery of agents specifically targeting the mutated cascades has provided a good response for patients with oncogenic B-Raf proto-оncogene, serine/threonine kinase (BRAF). However, numerous studies continue to focus on novel methods of treatment to overcome acquired resistance to novel drugs. Recently, it has been revealed that inhibition of endoplasmic reticulum (ER) stress chaperon 78 kDa glucose-regulated protein 78 (GRP78) leads to down-regulation of autophagy and increased sensitivity to temozolomide (TMZ) treatment...
May 9, 2018: Oncology Reports
Raymond Wu, Ramachandran Murali, Yasuaki Kabe, Samuel W French, Yi-Ming Chiang, Siyu Liu, Linda Sher, Clay C Wang, Stan Louie, Hidekazu Tsukamoto
Drug resistance is a major problem in the treatment of liver cancer. mTORC1 inhibitors have been tested for the treatment of liver cancer based on hyperactive mTOR in this malignancy. However, their clinical trials showed poor outcome due likely to their ability to upregulate CD133 and promote chemoresistance. CD133+ tumor initiating stem cell-like cells (TICs) isolated from mouse and human liver tumors are chemoresistant, and identification of an approach to abrogate this resistance is desired. In search for a compound which rescinds TIC's resistance to mTORC1 inhibition and improves chemotherapy, we identified baicalein (BC) which selectively chemosensitizes TICs and the human HCC cell line Huh7 cells but not mouse and human primary hepatocytes...
May 5, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Dongfang Tang, Dandan Zhao, Yun Wu, Ruyong Yao, Lin Zhou, Liming Lu, Wen Gao, Yifeng Sun
It is less known about miRNA3127-5p induced up-regulation of PD-L1, immune escape and drug resistance caused by increased PD-L1 in lung cancer. In this study, lentivirus was transduced into lung cancer cells, and quantitative PCR and Western blot were used to detect the expression of PD-L1. Then immunofluorescence assay was applied to detect autophagy, finally we explored the relationship between PD-L1 expressions and chemoresistance in patients. As a result, we found that microRNA-3127-5p promotes pSTAT3 to induce the expression of PD-L1; microRNA-3127-5p promotes STAT3 phosphorylation through suppressing autophagy, and autophagy could retaine pSTAT3 into the nucleus in miRNA-3127-5p knocked cells, and immune escape induced by elevated level of PD-L1 results in chemoresistance of lung cancer...
May 4, 2018: Journal of Cellular and Molecular Medicine
Dagmar Kolb-Lenz, Robert Fuchs, Birgit Lohberger, Ellen Heitzer, Katharina Meditz, Dominique Pernitsch, Elisabeth Pritz, Andrea Groselj-Strele, Andreas Leithner, Bernadette Liegl-Atzwanger, Beate Rinner
Chordoma is a rare tumor of the bone derived from remnants of the notochord with pronounced chemoresistance. A common feature of the notochord and chordoma cells is distinct vacuolization. Recently, the notochord vacuole was described as a lysosome-related organelle. Since lysosomes are considered as mediators of drug resistance in cancer, we were interested whether they may also play a role in chemoresistance of chordoma. We characterized the lysosomal compartment in chordoma cell lines by cytochemistry, electron microscopy (ELMI) and mutational analysis of genes essential for the physiology of lysosomes...
May 3, 2018: Histochemistry and Cell Biology
Kuan-Chen Lin, Mei-Wei Lin, Mu-Nung Hsu, Guan Yu-Chen, Yu-Chan Chao, Hsing-Yu Tuan, Chi-Shiun Chiang, Yu-Chen Hu
Rationale: Cisplatin (CDDP) is a broad-spectrum anticancer drug but chemoresistance to CDDP impedes its wide use for cancer therapy. Autophagy is an event occurring in the cytoplasm and cytoplasmic LC3 puncta formation is a hallmark of autophagy. Graphene oxide (GO) is a nanomaterial that provokes autophagy in CT26 colon cancer cells and confers antitumor effects. Here we aimed to evaluate whether combined use of GO with CDDP (GO/CDDP) overcomes chemoresistance in different cancer cells and uncover the underlying mechanism...
2018: Theranostics
Yizhou Zeng, Xiaofang Tian, Quan Wang, Weiyang He, Jing Fan, Xin Gou
Aim: The mammalian target of rapamycin (mTOR) pathway is a critical target for cancer treatment and the mTOR inhibitor everolimus (RAD001) has been approved for treatment of renal cell carcinoma (RCC). However, the limited efficacy of RAD001 has led to the development of drug resistance. Autophagy is closely related to cell survival and death, which may be activated under RAD001 stimulation. The aim of the present study was to identify the underlying mechanisms of RAD001 resistance in RCC cells through cytoprotective autophagy involving activation of the extracellular signal-regulated kinase (ERK) pathway...
2018: Drug Design, Development and Therapy
Xiaoyu Yang, Hubin Yin, Yunzhi Zhang, Xinyuan Li, Hang Tong, Yizhou Zeng, Quan Wang, Weiyang He
Overcoming the chemoresistance of bladder cancer is a pivotal obstacle in clinical treatments. Hypoxia widely exists in solid tumors and has been demonstrated to contribute to chemoresistance through hypoxia-inducible factor 1α (HIF‑1α)-mediated autophagy in several types of cancer. However, it is unclear whether HIF‑1α-mediated autophagy and chemoresistance occur in bladder cancer. The present study demonstrated that HIF‑1α was overexpressed in 20 bladder cancer tissues compared with matched paracarcinoma tissues...
April 24, 2018: International Journal of Oncology
Ka-Kui Chan, Oscar Gee-Wan Wong, Esther Shuk-Ying Wong, Karen Kar-Loen Chan, Philip Pun-Ching Ip, Ka-Yu Tse, Annie Nga-Yin Cheung
Ovarian clear cell carcinoma (OCCC) is a type of epithelial ovarian cancer that is strongly associated with endometriosis, resistance against conventional chemotherapy and thus poorer prognosis. The expression of inhibitory member of the ASPP family proteins (iASPP) and Polo-like kinase (PLK)1 were significantly higher in OCCC compared to benign cystadenomas and endometriosis. Both protein expressions were found to correlate with chemoresistance in patients with OCCC while high iASPP expression alone was significantly associated with a poor patient survival...
April 16, 2018: International Journal of Cancer. Journal International du Cancer
Siew-Li Lai, Mohd Rais Mustafa, Pooi-Fong Wong
BACKGROUND: Targeting autophagy is emerging as a promising strategy in cancer therapeutics in recent years. Autophagy can be modulated to drive cancer cell deaths that are notoriously resistant to apoptotic-inducing drugs. In addition, autophagy has been implicated as a prosurvival mechanism in mediating cancer chemoresistance. Our previous study has demonstrated that Panduratin A (PA), a plant-derived active compound exploits ER-stress-mediated apoptosis as its cytotoxic mechanism on melanoma...
March 15, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Ka-Kui Chan, Oscar Gee-Wan Wong, Esther Shuk-Ying Wong, Karen Kar-Loen Chan, Philip Pun-Ching Ip, Ka-Yu Tse, Annie Nga-Yin Cheung
Ovarian clear cell carcinoma (OCCC) is a type of epithelial ovarian cancer that is strongly associated with endometriosis, resistance against conventional chemotherapy and thus poorer prognosis. The expression of inhibitory member of the ASPP family proteins (iASPP) and Polo-like kinase (PLK)1 were significantly higher in OCCC compared to benign cystadenomas and endometriosis. Both protein expressions were found to correlate with chemoresistance in patients with OCCC while high iASPP expression alone was significantly associated with a poor patient survival...
April 12, 2018: International Journal of Cancer. Journal International du Cancer
Hangzhan Ma, Xiaoyang Li, Jinglu Wang, Francis J Hornicek, Cassandra C Garbutt, Xu Chang, Zhenfeng Duan
PURPOSE: Recent studies highlight the role of autophagy in cancer tumorigenesis, recurrence, metastasis, and chemoresistance. p62 is an adapter protein that is crucial for the autophagy pathway. In this study, we will describe the expression of p62 and its correlation with clinic prognosis in osteosarcoma. METHODS: Western blot was used to test the expression of p62 in osteosarcoma cell lines (U2OS, KHOS, MG63, Saos-2, U2OSR2, KHOSR2, and 143B). A tissue microarray (TMA) was analyzed by immunohistochemistry to determine the expression levels of p62 in osteosarcoma patients and evaluate any correlation between p62 and clinical characteristics in osteosarcoma patients...
April 4, 2018: Oncology
Mihwa Kim, Dae Joon Kim
The glycosylphosphatidylinositol-linked GDNF (glial cell derived neurotrophic factor) receptor alpha (GFRA), a coreceptor that recognizes the GDNF family of ligands, has a crucial role in the development and maintenance of the nervous system. Of the four identified GFRA isoforms, GFRA1 specifically recognizes GDNF and is involved in the regulation of proliferation, differentiation, and migration of neuronal cells. GFRA1 has also been implicated in cancer cell progression and metastasis. Recent findings show that GFRA1 can contribute to the development of chemoresistance in osteosarcoma...
April 4, 2018: International Journal of Molecular Sciences
J Andrew Livingston, Wei-Lien Wang, Jen-Wei Tsai, Alexander J Lazar, Cheuk Hong Leung, Heather Lin, Shailesh Advani, Najat Daw, Janice Santiago-O'Farrill, Mario Hollomon, Nancy B Gordon, Eugenie S Kleinerman
Chemotherapy-induced autophagy is a proposed mechanism of chemoresistance and potential therapeutic target in osteosarcoma. We evaluated heat shock protein 27 (HSP27) and autophagy-related proteins as predictors of pathologic treatment response and prognostic markers among osteosarcoma patients who received standard chemotherapy. We analyzed 394 tumor specimens (pre-treatment, post-treatment, and metastases) from 260 osteosarcoma patients by immunohistochemistry for cytoplasmic light chain 3B (LC3B)-positive puncta, sequestosome 1 (SQSTM1), high mobility group box 1 (HMGB1), and HSP27 expression...
March 28, 2018: Molecular Cancer Therapeutics
K Lohitesh, Rajdeep Chowdhury, Sudeshna Mukherjee
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality, accounting for almost 90% of total liver cancer burden. Surgical resection followed by adjuvant and systemic chemotherapy are the most meticulously followed treatment procedures but the complex etiology and high metastatic potential of the disease renders surgical treatment futile in majority of the cases. Another hindrance to the scenario is the acquired resistance to drugs resulting in relapse of the disease. Hence, to provide insights into development of novel therapeutic targets and diagnostic biomarkers, this review focuses on the various molecular mechanisms underlying chemoresistance in HCC...
2018: Cancer Cell International
Jin-Cheng Huang, Zhi-Fei Cui, Shui-Mu Chen, Lian-Jun Yang, Hong-Kai Lian, Bin Liu, Zhi-Hai Su, Jin-Shi Liu, Min Wang, Zheng-Bo Hu, Jia-Yao Ouyang, Qing-Chu Li, Hai Lu
Osteosarcoma(OS) remains a major health concern in childhood and adolescence, although cisplatin is one of the gold standard chemotherapeutic drugs in the treatment of OS, chemoresistant to cisplatin is common. Phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin inhibitor (mTOR) pathway and autophagy regulates chemosensitivity incancer cells. In this study, we hypothesized that NVP-BEZ235, a dual inhibitor of PI3K/mTOR, could synergize cisplatin sensitivity in OS. In vitro , NVP-BEZ235 plus cisplatinexerted a synergistic effect on cell proliferation inhibition and apoptosis induction...
February 13, 2018: Oncotarget
Dongfang Tang, Ruyong Yao, Dandan Zhao, Lin Zhou, Yun Wu, Yang Yang, Yifeng Sun, Liming Lu, Wen Gao
Insulin-like growth factor (IGF) signaling plays an important role in tumorigenesis and metastasis. Here, we analyzed insulin-like growth factor (IGF) binding protein-2 (IGFBP2) expression in 81 lung cancer patients and 36 controls consisting of healthy and benign pulmonary lesion participants for comparison, then validated the IGFBP2 expression in additional 84 lung cancer patients, and evaluated the prognostic and chemoresistant significance of IGFBP2 in two cohorts respectively. Next we detected the reversal effect of trichostatin A (TSA) on chemoresistance in cell lines with high IGFBP2 expression...
March 2, 2018: Scientific Reports
Kai Zhang, Jing Chen, Hao Zhou, Ying Chen, Yingru Zhi, Bei Zhang, Longbang Chen, Xiaoyuan Chu, Rui Wang, Chunni Zhang
Sorafenib is currently the only systemic agent approved for treatment of advanced hepatocellular carcinoma (HCC). However, intrinsic and acquired resistance to sorafenib remains a great challenge with respect to improving the prognoses of patients with HCC. The cyto-protective functions of autophagy have been suggested as a potential mechanism by which chemoresistance or targeted drug resistance occurs in tumour cells. In the present study, miR-142-3p was identified as a novel autophagy-regulating microRNA (miRNA) that plays a vital role in sorafenib resistance in HCC cells...
February 22, 2018: Cell Death & Disease
Chandan Kanta Das, Benedikt Linder, Florian Bonn, Florian Rothweiler, Ivan Dikic, Martin Michaelis, Jindrich Cinatl, Mahitosh Mandal, Donat Kögel
Target-specific treatment modalities are currently not available for triple-negative breast cancer (TNBC), and acquired chemotherapy resistance is a primary obstacle for the treatment of these tumors. Here we employed derivatives of BT-549 and MDA-MB-468 TNBC cell lines that were adapted to grow in the presence of either 5-Fluorouracil, Doxorubicin or Docetaxel in an aim to identify molecular pathways involved in the adaptation to drug-induced cell killing. All six drug-adapted BT-549 and MDA-MB-468 cell lines displayed cross resistance to chemotherapy and decreased apoptosis sensitivity...
March 2018: Neoplasia: An International Journal for Oncology Research
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