Telomerase reverse transcriptase promotes chemoresistance by suppressing cisplatin-dependent apoptosis in osteosarcoma cells

Zhang, Zhengpei; Yu, Ling; Dai, Guo; Xia, Kezhou; Liu, Gaiwei; Song, Qi; Tao, Chunjie; Gao, Tian; Guo, Weichun

doi:10.1038/s41598-017-07204-w

Cited by 30 publications

(27 citation statements)

References 40 publications

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“…To assess the effect of the combinatorial treatment on the immortalization of the PTES cells, the mRNA expression of the catalytic subunit hTERT was examined in the present study. Previous studies revealed that telomerase expression was increased in osteosarcoma cisplatin-resistant cells, thus leading to the suppression of cisplatin-induced apoptosis (50). However, hTERT expression was significantly decreased in the PTES cells in the present study.…”

Section: Discussioncontrasting

confidence: 60%

Glucose restriction combined with chemotherapy decreases telomere length and cancer antigen‑125 secretion in ovarian carcinoma

et al. 2019

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Although chemotherapy is the standard treatment for ovarian cancer (OC), recent studies have focused on its coupling with hypoglycemic drugs to decrease glucose availability. Similarly to cancer antigen 125 (Ca-125), telomerase, the key protein for telomere lengthening, is overexpressed in 90% of OC cases. The aim of the present study was to investigate the effect of the combination of glucose restriction and chemotherapy on telomere length and Ca-125 secretion in OC cells. SKOV-3, OVCAR-3 and Igrov-1 cells were treated with 20 µM cisplatin and 100 nM paclitaxel for 48 h in three different glucose concentrations: i) 4.5 g/l, ii) 1 g/l and iii) 0.5 g/l. The same treatment was repeated once per week for 6 consecutive weeks. The surviving cells were considered platinum-taxane escape (PTES) cells. The expression levels of telomerase and Ca-125 in treated and PTES cells were quantified by qPCR, and Ca-125 secretion by ELISA. Telomere length was evaluated by qPCR according to the Cawthon method. The modulation of Ca-125 by telomerase was assessed using inhibitors, small interfering RNA and transfection with human telomerase reverse transcriptase (hTERT) vectors. The implication of phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR) in Ca-125 modulation was investigated using specific inhibitors. An increase in hTERT and Ca-125 expression levels (range, 1.5-3 fold) was observed in short-term treated cells. However, an opposite effect was detected in PTES cells, where the rate of decrease in the expression levels of hTERT and Ca-125 reached 60% after treatment in 0.5 g/l glucose. Moreover, telomere length was decreased by 30% in cells treated with 0.5 g/l glucose. Inhibition of hTERT expression significantly decreased Ca-125 secretion, suggesting a potential modulation of Ca-125 by hTERT. The inhibition of the PI3K/Akt/mTOR pathway also decreased Ca-125 secretion; however, the effect of this treatment was not enhanced when coupled with telomerase inhibitors. In conclusion, the combination of chemotherapy and glucose restriction was observed to decrease Ca-125 secretion and telomerase expression leading to shortening in telomere length. Thus, decreasing glucose availability for OC cells during treatment may lead to a better clinical outcome and potentially improve the prognosis of patients with OC.

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Section: Discussioncontrasting

confidence: 60%

Glucose restriction combined with chemotherapy decreases telomere length and cancer antigen‑125 secretion in ovarian carcinoma

et al. 2019

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“…The data demonstrated that miR-192-5p mimics reduced chemo-resistance of osteosarcoma cells to cisplatin. And it had been reported that the cisplatin drug was presented the chemio-sensitivity in osteosarcoma cells ( 26 ).…”

Section: Resultsmentioning

confidence: 99%

MicroRNA-192-5p suppresses the initiation and progression of osteosarcoma by targeting USP1

et al. 2018

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Osteosarcoma is the most frequent primary malignant bone tumor. An increasing body of evidence has suggested that microRNAs (miRNA/miRs) have emerged as critical regulators in the initiation and progression of osteosarcoma. The present study explored the biological function of miR-192-5p and ubiquitin-specific protease 1 (USP1), and investigated whether miR-192-5p could directly interact with USP1 in osteosarcoma. The results revealed that miR-192-5p was significantly downregulated in osteosarcoma tissues and cell lines, while a reverse expression profile of USP1 was observed. Ectopic expression of miR-192-5p restrained cell proliferation, apoptosis, migration and invasion. In addition, it increased the sensitivity of osteosarcoma cells to cisplatin. USP1 was also observed to be a direct target gene of miR-192-5p in osteosarcoma. Overexpression of USP1 promoted cell proliferation, apoptosis, migration and invasion, and decreased cell chemo-sensitivity; however, it could be partially reversed via the overexpression of miR-192-5p in osteosarcoma cell lines. Taken together, the present study demonstrated that miR-192-5p suppressed the initiation and progression of osteosarcoma by targeting USP1. Therefore, miR-192-5p may serve as a valuable biomarker and the miR-192-5p/USP1 axis may function as a novel therapeutic target for osteosarcoma.

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“…4 The reasons for chemotherapy resistance in cancer treatment are multifaceted, and include the increased expression of ABC transporters (including MDR1, P-gp, MRP, and BCRP) and changes in cell membrane permeability that leads to drug efflux; impairment of DNA damage repair mechanisms; autophagymediated drug resistance; changes in tumor cell microenvironment; and mutations in drug targets. [5][6][7] Among these mechanisms, autophagy-mediated chemotherapy resistance has gained increasing attention. 5,6 Autophagy, a conservative life process in all eukaryotic cells, plays an important role in maintaining a stable intracellular environment and protein balance.…”

Section: Introductionmentioning

confidence: 99%

<p>Berberine Reverses Doxorubicin Resistance by Inhibiting Autophagy Through the PTEN/Akt/mTOR Signaling Pathway in Breast Cancer</p>

Wang

Liu

et al. 2020

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Berberine (BBR), a traditional Chinese medicine, has been shown effects on inhibiting cancer development. Autophagy-mediated resistance plays an important role in cancer progression; therefore, regulation of autophagy is a novel therapeutic strategy for cancer treatment. However, effects of BBR on autophagy-mediated resistance have not been reported. Methods: MCF-7 breast cancer cells and the doxorubicin (ADR)-resistant MCF-7 cells (MCF-7/ADR) were used for analyses. Western blotting was conducted to evaluate protein expression; MTT, colony formation, and EdU assays were conducted to assess cell proliferation; transmission electron microscopy was used to monitor autophagy levels; and a xenograft tumor model was established to assess the effects of BBR on reversing doxorubicin resistance. Results: We confirmed that BBR, recently identified as a suppressor of autophagy, inhibits autophagosome formation in MCF-7/ADR cells. Treatment with BBR blocked the accumulation of the autophagy-associated protein LC3II, resulting in cellular accumulation of p62, reduced cell proliferation, and reversal of doxorubicin resistance. Mechanistically, we found that BBR inhibited autophagy by modulating the PTEN/Akt/mTOR signaling pathway. In vivo, our study showed that BBR exerts clear anti-tumor effects. Conclusion: The results of this study suggest that BBR reverses doxorubicin resistance in breast cancer cells by inhibiting autophagy. This finding highlights the potential clinical application of BBR in the treatment of breast cancer.

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Telomerase reverse transcriptase promotes chemoresistance by suppressing cisplatin-dependent apoptosis in osteosarcoma cells

Cited by 30 publications

References 40 publications

Glucose restriction combined with chemotherapy decreases telomere length and cancer antigen‑125 secretion in ovarian carcinoma

Glucose restriction combined with chemotherapy decreases telomere length and cancer antigen‑125 secretion in ovarian carcinoma

MicroRNA-192-5p suppresses the initiation and progression of osteosarcoma by targeting USP1

<p>Berberine Reverses Doxorubicin Resistance by Inhibiting Autophagy Through the PTEN/Akt/mTOR Signaling Pathway in Breast Cancer</p>

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