Use of compounds inhibiting apelin / APJ / GP130 signaling for treating cancer
Today, despite current advances in combinatorial therapies such as surgery, radiotherapy and chemotherapy, aggressive cancers remain fatal. Cancer stem-like cells (CSCs) may account for chemotherapy resistance and thus represent a promising therapeutic target. In this context, the present inventors identified essential intracellular pathways favoring the self-renewal and survival of CSCs. More precisely, the present inventors showed that the cytokine co-receptor GP130 acts as a co-receptor for Apelin/APJ signaling and that the interaction of Apelin with APJ/GP130 activates a dual signaling pathway involving the Akt/mTOR and STAT3 transcription factor, thereby promoting CSCs survival and self-renewal. They therefore propose to block these pathways in order to treat patients suffering from tumors containing CSCs, such as glioblastomas. In another aspect, the invention relates to the use of the Apelin expression level for evaluating the survival probability of a subject suffering from glioblastoma.
1. A method for identifying compounds capable of inhibiting Cancer Stem Cells properties, wherein said properties are potency, self-renewal, and survival, said method comprising the steps:
a) contacting cells that have been transfected with exogenous nucleotide vectors expressing the co-receptors APJ and GP130 or are Cancer Stem Cells expressing the co-receptors APJ and GP130 with the Apelin polypeptide and a candidate compound,
b) detecting the activation level of an Apelin-dependent signaling pathway in the cells contacted in step a), and
c) detecting the activation level of an Apelin-dependent signaling pathway in cells that have been transfected with exogenous nucleotide vectors expressing the co-receptors APJ and GP130 or are Cancer Stem Cells expressing the co-receptors APJ and GP130 contacted only with the Apelin polypeptide;
wherein a candidate compound that impairs the activation level of an Apelin-dependent signaling pathway in cells from step a) as compared with cells from step c) is capable of inhibiting the potency and/or the self-renewal and/or the survival of Cancer Stem Cells.
2. The method of claim 1 , wherein detecting step b) comprises the detection and/or measurement of the activation level of an APJ-dependent signaling pathway.
3. The method of claim 2 , wherein activation of the APJ receptor is assessed by studying beta-arrestin2 recruitment to APJ.
4. The method of claim 2 , wherein said APJ-dependent signaling pathway is the Akt/mTOR signaling pathway.
5. The method of claim 1 , wherein detecting step b) comprises the detection and/or measurement of the activation level of a GP130-dependent signaling pathway.
6. The method of claim 1 , wherein said detecting step b) comprises the detection of the interaction between the co-receptors APJ and GP130.
7. The method of claim 1 , wherein the detecting step b) comprises the steps of:
b1) measuring the Apelin-dependent activation level of a GP130-dependent signaling pathway, and
b2) measuring the Apelin-dependent activation level of an APJ-dependent signaling pathway in said cells.
8. The method of claim 7 , wherein the detecting step b) comprises the steps of:
b1) measuring the Apelin-dependent activation level of the STAT3 signaling pathway in said cells, and
b2) measuring the Apelin-dependent beta-arrestin2 recruitment to APJ in said cells.
9. The method of claim 3 , wherein activation of the APJ receptor is assessed by studying beta-arrestin2 recruitment to APJ by Bioluminescence Resonance Energy Transfer.
10. A method for identifying compounds capable of inhibiting Cancer Stem Cells properties, wherein said properties are potency, self-renewal, and survival, said method comprising the steps:
a) contacting cells that have been transfected with exogenous nucleotide vectors expressing the co-receptors APJ and GP130 or are Cancer Stem Cells expressing the co-receptors APJ and GP130, with the Apelin polypeptide and a candidate compound,
b) detecting the activation level of an Apelin-dependent signaling pathway in the cells contacted in step a),
c) detecting the activation level of an Apelin-dependent signaling pathway in cells that have been transfected with exogenous nucleotide vectors expressing the co-receptors APJ and GP130 or are Cancer Stem Cells expressing the co-receptors APJ and GP130, contacted only with the Apelin polypeptide
d) selecting a candidate compound wherein the activation level of an Apelin-dependent signaling pathway is impaired in cells from step a) as compared with cells from step c), and
e) detecting if said selected candidate compound inhibits the potency and/or self-renewal and/or the survival of Cancer Stem Cells.