Oncolytic activity of Newcastle disease virus strain AF2240 in hypoxic cancer cells
Solid tumors have different microenvironment that can influence the capability of cancer treatments. Cancer cells in low oxygen condition or hypoxia, present an obstacle as they are more resistant towards chemotherapy and radiotherapy. The use of oncolytic viruses as therapeutic agent has demo...
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| Format: | Thesis |
| Language: | English |
| Published: |
2018
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| Subjects: | |
| Online Access: | http://psasir.upm.edu.my/id/eprint/75637/1/FBSB%202018%2038%20IR.pdf |
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| Summary: | Solid tumors have different microenvironment that can influence the capability of
cancer treatments. Cancer cells in low oxygen condition or hypoxia, present an obstacle
as they are more resistant towards chemotherapy and radiotherapy. The use of oncolytic
viruses as therapeutic agent has demonstrated promising results making it an ideal
approach to treat cancer cells. Newcastle disease virus (NDV) is an oncolytic virus that
has specificity in targeting tumor cells over normal cells. Despite its potential, the exact
mechanism of its oncolysis in hypoxic cancer cells remains unknown. In the present
study, the oncolytic activity of NDV in hypoxic cancer cells was investigated. Various
cancer cell lines such as osteosarcoma (Saos-2), breast carcinoma (MCF-7) and
fibrosarcoma (HT1080) cells were infected with NDV under normoxic or hypoxic
conditions. Following NDV infection, molecular, proteomic, immunological and
biochemical techniques were performed. Data obtained in this study showed that NDV
was capable to infect and replicate in hypoxia tumor microenvironment similar to
normoxia. This was confirmed by the equivalent level of NP viral protein expressed in
normoxic and hypoxic conditions of Saos-2, MCF-7 and HT1080 cells. The amount of
NP viral protein detected in the infected cells was correlated with the production of the
viral progeny. It was observed that NDV replicates in hypoxic cancer cells to levels
comparable to normoxic cells, leading to induction in cytopathic effects which
subsequently caused cell death. MCF-7 cells which displayed better replication upon
NDV infection resulted in more cytotoxicity than in Saos-2 and HT1080 cells. These
data provide evidence that NDV was able to adapt and exhibit an oncolytic capacity in
hypoxic tumor cells in a manner that is equivalent to the normoxic tumor cells and was
cell type specific. Hypoxic tumor cells negatively affect therapeutic outcome by
overexpressing pro-survival genes under the control of the hypoxia-inducible factor
(HIF). HIF-1 is a heterodimer transcriptional factor consisting of a regulated α (HIF-
1α) and constitutive β subunit (HIF-1β). Overexpression of HIF contributes to an
aggressive malignancy, which is associated with chemoresistance and radioresistance.
In the present study, the effects of NDV infection on HIF-1α in cancer cells were
examined. Data obtained showed that a velogenic NDV infection diminished hypoxiainduced
HIF-1α accumulation, leading to a decreased activation of its downstream
target gene, carbonic anhydrase 9 (CA9). This NDV-induced down regulation of HIF 1α occurred post-translationally and was partially abrogated by proteasomal inhibition.
The process appeared to be independent of the tumor suppressor protein, p53. Apart
from the ability of NDV in targeting hypoxic cancer cells and HIF-1α, the significance
of hypoxia in the antiviral response towards NDV infection was also evaluated in this
study. Data obtained showed that IFN-β is the principal antiviral factor produced by
cells in response to NDV infection. Hypoxic condition was observed to minimally
affect the levels of IFN-β production in MCF-7 cells, but not in Saos-2 and HT1080
cells. NDV infection in hypoxic conditions did not drastically alter the level of IFN-β
production including STAT proteins. In addition, NDV induced IFN-β secretion results
in increased levels of total STAT1 and STAT1 phosphorylation proteins leading to cell
death. In summary, this study demonstrated that NDV infection down regulates HIF-1α
and induced cell death in hypoxic tumor cells comparable to normoxic with the
involvement of IFN-β signalling. These findings also help in improving the existing
data regarding the efficiency of NDV as a promising therapeutic agent to infect and
eliminate various types of cells in different tumor microenvironments, particularly in
hypoxic cancer cells. |
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