An active IGF-1R-AKT signaling imparts functional heterogeneity in ovarian CSC population.
Deregulated IGF-1R-AKT signaling influences multiple nodes of cancer cell physiology and assists in migration, metastasis and acquirement of radio/chemoresistance. Enrichment of cancer stem cells (CSC) positively correlates with radio/chemoresistance development in various malignancies. It is unclear though, how IGF-1R-AKT signalling shapes CSC functionality especially in ovarian cancer. Previously we showed that upregulated IGF-1R expression is essential to initiate platinum-taxol resistance at early stage which declines with elevated levels of activated AKT at late resistant stage in ovarian cancer cells. Here, we investigated the effect of this oscillatory IGF-1R-AKT signalling upon CSC functionality during generation of chemoresistance. While gradual increase in CSC properties from early (ER) to late (LR) resistant stages was observed in three different (cisplatin/paclitaxel/cisplatin-paclitaxel) cellular models created in two ovarian cancer cell lines, the stemness gene expressions (oct4/sox2/nanog) reached a plateau at early resistant stages. Inhibition of IGF-1R only at ER and AKT inhibition only at LR stages significantly abrogated the CSC phenotype. Interestingly, real time bioluminescence imaging showed CSCs of ER stages possessed faster tumorigenic potential than CSCs belonging to LR stages. Together, our data suggest that IGF-1R-AKT signalling imparts functional heterogeneity in CSCs during acquirement of chemoresistance in ovarian carcinoma.
Imaging Cell Signaling and Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India.
Ram K
RK
Singh
Imaging Cell Signaling and Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India.
Ajit
A
Dhadve
Imaging Cell Signaling and Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India.
Asmita
A
Sakpal
Molecular Functional Imaging Laboratory, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India.
Abhijit
A
De
Imaging Cell Signaling and Therapeutics Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, Maharashtra, India.
Pritha
P
Ray
D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt