Inhibition of c-Met activation sensitizes osteosarcoma cells to cisplatin via suppression of the PI3K–Akt signaling

Wang, Kelai; Zhuang, Yan; Liu, Chunlan; Li, Yang

doi:10.1016/j.abb.2012.07.003

Cited by 39 publications

(29 citation statements)

References 26 publications

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“…Wang et al confirmed that suppression of the PI3K/AKT signaling can effectively sensitize osteosarcoma cells to cisplatin [36]. Our results also showed that combination of CDDP and 5-Fu inhibited the activity of PI3K/Akt pathway; DNA-PKcs siRNA could effectively suppress the expression of DNA-PKcs and further reduced the activity of PI3K/Akt signaling, which may be associated with sensitization of HepG2 cells to combination treatment of CDDP and 5-Fu.…”

Section: Discussionsupporting

confidence: 86%

DNA-PKcs deficiency sensitizes the human hepatoma HepG2 cells to cisplatin and 5-fluorouracil through suppression of the PI3K/Akt/NF-κB pathway

et al. 2014

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The aim of the present study was to investigate the effects of DNA-PKcs deficiency on the chemosensitivity of human hepatoma HepG2 cells to cisplatin (CDDP) and 5-fluorouracil (5-Fu), and to explore the underlying molecular mechanism. After transfection with DNA-PKcs siRNA or control siRNA, HepG2 cells were exposed to combination treatment of CDDP and 5-Fu. The cell viability, DNA damage, cell apoptosis, intracellular reactive oxygen species and glutathione (GSH) level, expression of apoptosis related proteins, activity of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, and nuclear factor-κB (NF-κB) pathways were assessed. The combination of CDDP and 5-Fu had a synergistic cytotoxic effect in HepG2 cells in terms of the cell viability, DNA damage, apoptosis, and oxidative stress level. DNA-PKcs siRNA could sensitize the HepG2 cells to the combined treatment. DNA-PKcs suppression further reduced the Akt phosphorylation level and Bcl-2 expression in HepG2 cells exposed to CDDP and 5-Fu, but enhanced the expression of pro-apoptotic proteins p53 and caspase-3. Moreover, CDDP could inhibit the transcriptional activity of NF-κB through degradation of IkB-α, while 5-Fu alone seemed in some extent increases the NF-κB activity. The combined treatment with CDDP and 5-Fu resulted in significantly decrease of the transcriptional activity of NF-κB, which was further aggravated by DNA-PKcs siRNA treatment. In conclusion, DNA-PKcs suppression had complementary effects in combination with CDDP and 5-Fu treatment in HepG2 cells, which was associated with suppression of NF-κB signaling pathway cascade, activation of caspase-3 and p53, as well as down-regulation of Bcl-2 and GSH.

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Section: Discussionsupporting

confidence: 86%

DNA-PKcs deficiency sensitizes the human hepatoma HepG2 cells to cisplatin and 5-fluorouracil through suppression of the PI3K/Akt/NF-κB pathway

et al. 2014

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“…p70S6K expression, a measure of pathway activity, is present in 70-80% of OS and the level of expression has been correlated with overall and disease-free survival (51). Activation of PI3K-AKT signaling is downstream of several biological processes involved in OS metastasis, such as c-Met and Ezrin expression (52,53). Micro-RNA-221, expressed at high levels in OS targets PTEN, increases cell survival, decreases apoptosis, and induces cisplatin resistance (54).…”

Section: Discussionmentioning

confidence: 99%

Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma

Perry

Kiežun

Tonzi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

378

382

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Osteosarcoma is the most common primary bone tumor, yet there have been no substantial advances in treatment or survival in three decades. We examined 59 tumor/normal pairs by whole-exome, whole-genome, and RNA-sequencing. Only the TP53 gene was mutated at significant frequency across all samples. The mean nonsilent somatic mutation rate was 1.2 mutations per megabase, and there was a median of 230 somatic rearrangements per tumor. Complex chains of rearrangements and localized hypermutation were detected in almost all cases. Given the intertumor heterogeneity, the extent of genomic instability, and the difficulty in acquiring a large sample size in a rare tumor, we used several methods to identify genomic events contributing to osteosarcoma survival. Pathway analysis, a heuristic analytic algorithm, a comparative oncology approach, and an shRNA screen converged on the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway as a central vulnerability for therapeutic exploitation in osteosarcoma. Osteosarcoma cell lines are responsive to pharmacologic and genetic inhibition of the PI3K/mTOR pathway both in vitro and in vivo., the most common primary bone tumor, is an aggressive cancer that affects children, adolescents, and young adults. In contrast to the improvements in 5-year overall survival for childhood cancers from 58% to 82% in the past three decades, the overall survival for pediatric OS has remained static over that same time period at 60% (1, 2).Predisposition to OS is associated with germline syndromes, including hereditary retinoblastoma and Li-Fraumeni syndrome (3, 4). OS is also seen in syndromes with mutations in RECQ helicases and SQSTM1 (5, 6). However, most cases of OS develop sporadically and are characterized by complex genomics. The first genome-wide association study conducted in OS only identified two susceptibility loci implicating one gene, GRM4, a glutamate receptor (7).Linkage with hereditary retinoblastoma and Li Fraumeni led to the recognition of recurrent somatic alterations in TP53, RB1, and genes interacting with TP53 and RB1 in OS (8, 9). Candidate-gene approaches demonstrated recurrent somatic mutations, deletions, and rearrangement affecting TP53 (9). Additional mechanisms of p53 inactivation described in OS are MDM2 and COPS3 amplification (8, 9). RB1 mutations are present in 6% and deletions or structural alterations are seen in 40% of cases (10,11). CDKN2A is deleted in 10-20% of OS (9, 12). Multiple other cancer-associated genes have been reported to be altered in OS [reviewed in Kansara and Thomas (5)]. Many of these studies SignificanceWe present, to our knowledge, the first comprehensive nextgeneration sequencing of osteosarcoma in combination with a functional genomic screen in a genetically defined mouse model of osteosarcoma. Our data provide a strong rationale for targeting the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in osteosarcoma and a foundation for rational clinical trial design. These findings present an immed...

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“…Surface receptors ERBB2/HER2 and MET/c-MET and their downstream effectors AKT, MAPK/ERK, and SRC, have been implicated in the progression and metastasis of osteosarcomas. [39][40][41][42] The effects of NSC185058 on kinase activities were determined by assessing the phosphorylation states of these kinases in cells growing in nutrient-and serum-rich medium (Fig. S6).…”

Section: Effects Of Nsc185058 On the Growth Of Osteosarcoma Tumorsmentioning

confidence: 99%

A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors

et al. 2014

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Autophagy has been implicated in the progression and chemoresistance of various cancers. In this study, we have shown that osteosarcoma Saos-2 cells lacking ATG4B, a cysteine proteinase that activates LC3B, are defective in autophagy and fail to form tumors in mouse models. By combining in silico docking with in vitro and cell-based assays, we identified small compounds that suppressed starvation-induced protein degradation, LC3B lipidation, and formation of autophagic vacuoles. NSC185058 effectively inhibited ATG4B activity in vitro and in cells while having no effect on MTOR and PtdIns3K activities. In addition, this ATG4B antagonist had a negative impact on the development of Saos-2 osteosarcoma tumors in vivo. We concluded that tumor suppression was due to a reduction in ATG4B activity, since we found autophagy suppressed within treated tumors and the compound had no effects on oncogenic protein kinases. Our findings demonstrate that ATG4B is a suitable anti-autophagy target and a promising therapeutic target to treat osteosarcoma.

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Inhibition of c-Met activation sensitizes osteosarcoma cells to cisplatin via suppression of the PI3K–Akt signaling

Cited by 39 publications

References 26 publications

DNA-PKcs deficiency sensitizes the human hepatoma HepG2 cells to cisplatin and 5-fluorouracil through suppression of the PI3K/Akt/NF-κB pathway

DNA-PKcs deficiency sensitizes the human hepatoma HepG2 cells to cisplatin and 5-fluorouracil through suppression of the PI3K/Akt/NF-κB pathway

Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma

A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors

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