Telomerase Inhibition Decreases Alpha-Fetoprotein Expression and Secretion by Hepatocellular Carcinoma Cell Lines: In Vitro and In Vivo Study

Tahtouh, Roula; Azzi, Anne-Sophie; Alaaeddine, Nada; Chamat, Soulaïma; Bouharoun-Tayoun, Hasnaa; Wardi, Layal; Raad, Issam; Sarkis, Riad; Antoun, Najibe Abou; Hilal, George

doi:10.1371/journal.pone.0119512

Cited by 21 publications

(11 citation statements)

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“…The inclusion of telomerase inhibitors in chemotherapy protocols for cancer patients may have strong effects on cell proliferation and survival and thus may represent a valid strategy to complement current treatment modalities, as also suggested by others. 42, 43 Confirmation of these findings in primary tumors cells from patients with EBV-driven and unrelated B-cell malignancies and in suitable animal models will pave the way for a solidly based pre-clinical rationale for including TERT inhibitors in chemotherapy protocols for the treatment of these malignancies.…”

Section: Discussionmentioning

confidence: 84%

Short-term inhibition of TERT induces telomere length-independent cell cycle arrest and apoptotic response in EBV-immortalized and transformed B cells

et al. 2016

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Besides its canonical role in stabilizing telomeres, telomerase reverse transcriptase (TERT) may promote tumorigenesis through extra-telomeric functions. The possible therapeutic effects of BIBR1532 (BIBR), a powerful TERT inhibitor, have been evaluated in different cellular backgrounds, but no data are currently available regarding Epstein–Barr virus (EBV)-driven B-cell malignancies. Our aim was to characterize the biological effects of TERT inhibition by BIBR on EBV-immortalized lymphoblastoid cell lines (LCLs) and fully transformed Burkitt's lymphoma (BL) cell lines. We found that BIBR selectively inhibits telomerase activity in TERT-positive 4134/Late and 4134/TERT+ LCLs and EBV-negative BL41 and EBV-positive BL41/B95.8 BL cell lines. TERT inhibition led to decreased cell proliferation, accumulation of cells in the S-phase and ultimately to increased apoptosis, compared with mock-treated control cells. All these effects occurred within 72 h and were not observed in BIBR-treated TERT-negative 4134/TERT- and U2OS cells. The cell cycle arrest and apoptosis, consequent upon short-term TERT inhibition, were associated with and likely dependent on the activation of the DNA damage response (DDR), highlighted by the increased levels of γH2AX and activation of ATM and ATR pathways. Analyses of the mean and range of telomere lengths and telomere dysfunction-induced foci indicated that DDR after short-term TERT inhibition was not related to telomere dysfunction, thus suggesting that TERT, besides stabilizing telomere, may protect DNA via telomere-independent mechanisms. Notably, TERT-positive LCLs treated with BIBR in combination with fludarabine or cyclophosphamide showed a significant increase in the number of apoptotic cells with respect to those treated with chemotherapeutic agents alone. In conclusion, TERT inhibition impairs cell cycle progression and enhances the pro-apoptotic effects of chemotherapeutic agents in TERT-positive cells. These results support new therapeutic applications of TERT inhibitors in EBV-driven B-cell malignancies.

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Section: Discussionmentioning

confidence: 84%

Short-term inhibition of TERT induces telomere length-independent cell cycle arrest and apoptotic response in EBV-immortalized and transformed B cells

et al. 2016

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“…All the analyzes presented were performed in two HCC cell lines characterized by a different secretion of AFP and DCP, two markers associated with HCC cell growth and motility. PLC/PRF/5 cells are characterized by low levels of AFP secretion and high DCP, whereas HepG2 cells by contrast secrete high levels of AFP [11] and low of DCP (see Materials and Methods section). The secreted levels of AFP and DCP in the cell culture medium were measured after 48 h of treatments described.…”

Section: Resultsmentioning

confidence: 99%

Ramucirumab and GSK1838705A Enhance the Inhibitory Effects of Low Concentration Sorafenib and Regorafenib Combination on HCC Cell Growth and Motility

D’Alessandro

Refolo

Iacovazzi

et al. 2019

Cancers

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Several new multikinase inhibitors have recently been introduced into clinical practice for hepatocellular carcinoma (HCC) therapy. Small increases in survival were reported as well as considerable toxicity. There is thus a need for effective therapies with lower toxicities. We examined whether a combination of sorafenib and regorafenib might also be effective at very low concentrations, with resulting potential for lessened clinical toxicity. MTT test, clonogenic assay, Ki67 staining and cell cycle analysis were assessed for cell proliferation and Annexin V and western blotting analysis relative to the expression of cleaved Caspase-3 and BID for cell apoptosis. In these experimental conditions cell growth and migration were potently inhibited and apoptosis induced even in HCC cells producing high alpha fetoprotein (AFP) levels (clinically worse prognosis). The combination also inhibited levels of the two HCC biomarkers, AFP and des gamma carboxy prothrombin (DCP). Additional inhibition of Vascular Endothelial Growth Factor Receptor (VEGFR) or Insulin-like Growth Factor 1 Receptor (IGF1R) enhanced effects on AFP and DCP levels, cell growth inhibition and MAPK and PI3K/Akt signaling inhibition due to sorafenib/regorafenib combination. These combinations have the potential for decreased toxicity while simultaneously enhancing therapeutic effects. This potential decrease in toxicity is being explored in ongoing studies.

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“…TERT extends telomeres and TERT mutations activate this activity, allowing cells to continue dividing. TERT alterations are one of the earliest genomic anomalies involved in malignant transformation in HCC and may, therefore, be considered as a tumor “gatekeeper.” [ 46 ] Tahtouh and colleagues demonstrated that telomerase inhibition decreases alpha fetoprotein (AFP) expression in individuals with HCC and may have a suppressive effect on cell growth via attenuation of telomere repair [ 49 ]. Unfortunately, low-dose cyclophosphamide administration followed by GV1001 vaccinations (GV1001 being a telomerase vaccine) did not demonstrate efficacy [ 50 ].…”

Section: Signaling Pathwaysmentioning

confidence: 99%

The biology of Hepatocellular carcinoma: implications for genomic and immune therapies

Khemlina

Ikeda

Kurzrock³

2017

Mol Cancer

369

250

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Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is a leading cause of cancer-related death worldwide. It is highly refractory to most systemic therapies. Recently, significant progress has been made in uncovering genomic alterations in HCC, including potentially targetable aberrations. The most common molecular anomalies in this malignancy are mutations in the TERT promoter, TP53, CTNNB1, AXIN1, ARID1A, CDKN2A and CCND1 genes. PTEN loss at the protein level is also frequent. Genomic portfolios stratify by risk factors as follows: (i) CTNNB1 with alcoholic cirrhosis; and (ii) TP53 with hepatitis B virus-induced cirrhosis. Activating mutations in CTNNB1 and inactivating mutations in AXIN1 both activate WNT signaling. Alterations in this pathway, as well as in TP53 and the cell cycle machinery, and in the PI3K/Akt/mTor axis (the latter activated in the presence of PTEN loss), as well as aberrant angiogenesis and epigenetic anomalies, appear to be major events in HCC. Many of these abnormalities may be pharmacologically tractable. Immunotherapy with checkpoint inhibitors is also emerging as an important treatment option. Indeed, 82% of patients express PD-L1 (immunohistochemistry) and response rates to anti-PD-1 treatment are about 19%, and include about 5% complete remissions as well as durable benefit in some patients. Biomarker-matched trials are still limited in this disease, and many of the genomic alterations in HCC remain challenging to target. Future studies may require combination regimens that include both immunotherapies and molecularly matched targeted treatments.

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Telomerase Inhibition Decreases Alpha-Fetoprotein Expression and Secretion by Hepatocellular Carcinoma Cell Lines: In Vitro and In Vivo Study

Cited by 21 publications

References 77 publications

Short-term inhibition of TERT induces telomere length-independent cell cycle arrest and apoptotic response in EBV-immortalized and transformed B cells

Short-term inhibition of TERT induces telomere length-independent cell cycle arrest and apoptotic response in EBV-immortalized and transformed B cells

Ramucirumab and GSK1838705A Enhance the Inhibitory Effects of Low Concentration Sorafenib and Regorafenib Combination on HCC Cell Growth and Motility

The biology of Hepatocellular carcinoma: implications for genomic and immune therapies

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