The ubiquitous second messenger Ca
has long been recognized as a key regulator in cell migration. Locally confined Ca
, in particular, is essential for building front-to-rear Ca
gradient, which ...serves to maintain the morphologic polarity required in directionally migrating cells. However, little is known about the source of the Ca
and the mechanism by which they crosstalk between different signaling pathways in cancer cells. Here, we report that calcium release-activated calcium modulator 2 (ORAI2), a poorly characterized store-operated calcium (SOC) channel subunit, predominantly upregulated in the lymph node metastasis of gastric cancer, supports cell proliferation and migration. Clinical data reveal that a high frequency of ORAI2-positive cells in gastric cancer tissues significantly correlated with poor differentiation, invasion, lymph node metastasis, and worse prognosis. Gain- and loss-of-function showed that ORAI2 promotes cell motility, tumor formation, and metastasis in both gastric cancer cell lines and mice. Mechanistically, ORAI2 mediated SOC activity and regulated tumorigenic properties through the activation of the PI3K/Akt signaling pathways. Moreover, ORAI2 enhanced the metastatic ability of gastric cancer cells by inducing FAK-mediated MAPK/ERK activation and promoted focal adhesion disassembly at rear-edge of the cell. Collectively, our results demonstrate that
is a novel gene that plays an important role in the tumorigenicity and metastasis of gastric cancer. SIGNIFICANCE: These findings describe the critical role of ORAI2 in gastric cancer cell migration and tumor metastasis and uncover the translational potential to advance drug discovery along the ORAI2 signaling pathway.
Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders ...the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.
Here, the anti-malarial activity of two gold(i) phosphine compounds auranofin and Au(d2pype)
Cl (where d2pype is 1,2-bis(di-2-pyridylphosphino)ethane), were examined to inform their use as potential ...drugs and malaria parasite-attenuating agents. In vitro, the gold compounds were active against Plasmodium falciparum and P. knowlesi as well as the rodent parasite P. chabaudi AS. Attenuation of the parasite was observed when mice were inoculated with P. chabaudi AS infected red blood cells treated in vitro with Au(d2pype)
Cl (1 or 2 μM) or auranofin (2 μM) for 2 or 3 h. Quantitative PCR data showed persistence of low levels of parasite DNA up to 8 days post inoculation. In some experiments, there was microscopically detectable parastiemia following inoculation which subsequently cleared. Following 1 or 3 doses of gold compound-treated parasitized red blood cells (pRBCs), protection was not observed when these mice were subsequently challenged with wild type P. chabaudi AS. In experiments where microscopically detectable parasites were observed following in vivo inoculation, mice were subsequently fully protected against a challenge infection with wildtype parasites. In an infect-and-treat rodent model, the gold compounds were unable to inhibit P. chabaudi AS growth in vivo when administered orally. Gold compounds act via the inhibition of antioxidant systems which are critical in the pathogen's survival from attack by the host oxidants. In vitro, they directly inhibit the parasite thioredoxin reductase, hence the observed suppressive activity. On the other hand, in vivo, the gold compounds may not be readily available for absorption and thus pharmacokinetic studies will be required to further examine drug bioavailability following administration. With structural differences in redox mechanisms of P. falciparum and the human host being identified, gold compounds can be better designed to more efficiently target and selectively inhibit the parasite.
Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders ...the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.
Here, the anti-malarial activity of two gold(
i
) phosphine compounds auranofin and Au(d2pype)
2
Cl (where d2pype is 1,2-bis(di-2-pyridylphosphino)ethane), were examined to inform their use as ...potential drugs and malaria parasite-attenuating agents.
In vitro
, the gold compounds were active against
Plasmodium falciparum
and
P. knowlesi
as well as the rodent parasite
P. chabaudi AS
. Attenuation of the parasite was observed when mice were inoculated with
P. chabaudi AS
infected red blood cells treated
in vitro
with Au(d2pype)
2
Cl (1 or 2 μM) or auranofin (2 μM) for 2 or 3 h. Quantitative PCR data showed persistence of low levels of parasite DNA up to 8 days post inoculation. In some experiments, there was microscopically detectable parastiemia following inoculation which subsequently cleared. Following 1 or 3 doses of gold compound-treated parasitized red blood cells (pRBCs), protection was not observed when these mice were subsequently challenged with wild type
P. chabaudi AS
. In experiments where microscopically detectable parasites were observed following
in vivo
inoculation, mice were subsequently fully protected against a challenge infection with wildtype parasites. In an infect-and-treat rodent model, the gold compounds were unable to inhibit
P. chabaudi AS
growth
in vivo
when administered orally. Gold compounds act
via
the inhibition of antioxidant systems which are critical in the pathogen's survival from attack by the host oxidants.
In vitro
, they directly inhibit the parasite thioredoxin reductase, hence the observed suppressive activity. On the other hand,
in vivo
, the gold compounds may not be readily available for absorption and thus pharmacokinetic studies will be required to further examine drug bioavailability following administration. With structural differences in redox mechanisms of
P. falciparum
and the human host being identified, gold compounds can be better designed to more efficiently target and selectively inhibit the parasite.
The asexual blood-stage
Plasmodium
parasite attenuating properties of gold(
i
) phosphine compounds are exploited in a novel strategy for malaria vaccine development.
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