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Prolonged inhibition of class I PI3K promotes liver cancer stem cell expansion by augmenting SGK3/GSK-3?/?-catenin signalling.

ABSTRACT: BACKGROUND:Serum and glucocorticoid-regulated kinase 3 (SGK3) has been reported to play an important role in tumour progression, but its role in cancer stem cells (CSCs) remains obscure. The phosphoinositide 3-kinase (PI3K) pathway is considered a hallmark of cancer. Although many PI3K pathway-targeted therapies have been tested in oncology trials, the results are not satisfactory. METHODS:We used spheroids cultured in serum-free culture medium and MicroBead isolation to obtain liver CSCs. Spheroid formation assay and flow cytometric analysis were performed to investigate liver CSC expansion. Real-time polymerase chain reaction (PCR), western blot and immunofluorescence were used to assess gene expression in cell lines. RESULTS:We found that SGK3 is preferentially activated in liver CSCs. Upregulated SGK3 significantly increases the expansion of liver CSCs. Conversely, suppression of SGK3 in human hepatocarcinoma (HCC) cells had an opposite effect. Mechanistically, SGK3 promoted ?-catenin accumulation by suppressing GSK-3?-mediated ?-catenin degradation in liver CSCs, and then promoting the expansion of liver CSCs. Prolonged treatment of HCC cells with class I PI3K inhibitors leads to activation of SGK3 and expansion of liver CSCs. Inhibition of hVps34 can block SGK3 activity and suppress liver CSC expansion induced by PI3K inhibitors. More importantly, we also found that prolonged treatment of HCC cells with PI3K inhibitors stimulates the ?-catenin signalling pathway via activation of SGK3. CONCLUSIONS:Prolonged inhibition of class I PI3K promotes liver CSC expansion by augmenting SGK3-dependent ?-catenin stabilisation, and effective inhibition of SGK3 signalling may be useful in eliminating liver CSCs and in PI3K pathway-targeted cancer therapies.

SUBMITTER: Liu F

PROVIDER: S-EPMC6020243 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Prolonged inhibition of class I PI3K promotes liver cancer stem cell expansion by augmenting SGK3/GSK-3β/β-catenin signalling.

Liu Fengchao F Wu Xiaoling X Jiang Xin X Qian Yanzhi Y Gao Jian J

Journal of experimental & clinical cancer research : CR 20180625 1

<h4>Background</h4>Serum and glucocorticoid-regulated kinase 3 (SGK3) has been reported to play an important role in tumour progression, but its role in cancer stem cells (CSCs) remains obscure. The phosphoinositide 3-kinase (PI3K) pathway is considered a hallmark of cancer. Although many PI3K pathway-targeted therapies have been tested in oncology trials, the results are not satisfactory.<h4>Methods</h4>We used spheroids cultured in serum-free culture medium and MicroBead isolation to obtain li ...[more]

PMID: 29940988

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Project description:BackgroundNeural stem cells (NSCs) are considered as candidates for cell replacement therapy in many neurological disorders. However, the propensity for their differentiation to proceed more glial rather than neuronal phenotypes in pathological conditions limits positive outcomes of reparative transplantation. Exogenous physical stimulation to favor the neuronal differentiation of NSCs without extra chemical side effect could alleviate the problem, providing a safe and highly efficient cell therapy to accelerate neurological recovery following neuronal injuries.ResultsWith 7-day physiological electric field (EF) stimulation at 100 mV/mm, we recorded the boosted neuronal differentiation of NSCs, comparing to the non-EF treated cells with 2.3-fold higher MAP2 positive cell ratio, 1.6-fold longer neuronal process and 2.4-fold higher cells ratio with neuronal spontaneous action potential. While with the classical medium induction, the neuronal spontaneous potential may only achieve after 21-day induction. Deficiency of either PI3Kγ or β-catenin abolished the above improvement, demonstrating the requirement of the PI3K/Akt/GSK-3β/β-catenin cascade activation in the physiological EF stimulation boosted neuronal differentiation of NSCs. When transplanted into the spinal cord injury (SCI) modelled mice, these EF pre-stimulated NSCs were recorded to develop twofold higher proportion of neurons, comparing to the non-EF treated NSCs. Along with the boosted neuronal differentiation following transplantation, we also recorded the improved neurogenesis in the impacted spinal cord and the significantly benefitted hind limp motor function repair of the SCI mice.ConclusionsIn conclusion, we demonstrated physiological EF stimulation as an efficient method to boost the neuronal differentiation of NSCs via the PI3K/Akt/GSK-3β/β-catenin activation. Pre-treatment with the EF stimulation induction before NSCs transplantation would notably improve the therapeutic outcome for neurogenesis and neurofunction recovery of SCI.

Dataset Information

Prolonged inhibition of class I PI3K promotes liver cancer stem cell expansion by augmenting SGK3/GSK-3?/?-catenin signalling.

Publications

Prolonged inhibition of class I PI3K promotes liver cancer stem cell expansion by augmenting SGK3/GSK-3β/β-catenin signalling.

Similar Datasets

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