Abstract
BackgroundProteins that are required for anchorage-independent survival of tumor cells represent attractive targets for therapeutic intervention since this property is believed to be critical for survival of tumor cells displaced from their natural niches. Anchorage-independent survival is induced by growth factor receptor hyperactivation in many cell types. We aimed to identify molecules that critically regulate IGF-1-induced anchorage-independent survival.Methods and ResultsWe conducted a high-throughput siRNA screen and identified PTK6 as a critical component of IGF-1 receptor (IGF-1R)-induced anchorage-independent survival of mammary epithelial cells. PTK6 downregulation induces apoptosis of breast and ovarian cancer cells deprived of matrix attachment, whereas its overexpression enhances survival. Reverse-phase protein arrays and subsequent analyses revealed that PTK6 forms a complex with IGF-1R and the adaptor protein IRS-1, and modulates anchorage-independent survival by regulating IGF-1R expression and phosphorylation. PTK6 is highly expressed not only in the previously reported Her2+ breast cancer subtype, but also in high grade ER+, Luminal B tumors and high expression is associated with adverse outcomes.ConclusionsThese findings highlight PTK6 as a critical regulator of anchorage-independent survival of breast and ovarian tumor cells via modulation of IGF-1 receptor signaling, thus supporting PTK6 as a potential therapeutic target for multiple tumor types. The combined genomic and proteomic approaches in this report provide an effective strategy for identifying oncogenes and their mechanism of action.
Highlights
Adhesion to extracellular matrix (ECM) provides epithelial cells with critical cues about their environment that are required for their proliferation, survival and tissue organization
To identify genes that are required for induced anchorage-independent survival, IGF-1 receptor (IGF-1R) cells were transfected in suspension cultures with a library of individual siRNA oligonucleotides targeting all human kinases and related proteins (Figure 1B)
PTK6 modulates IGF-1 dependent anoikis resistance PTK6 was identified as a ‘‘high-confidence’’ candidate gene because multiple siRNA oligonucleotides caused a significant, preferential inhibition of IGF-1R-driven anchorage-independent viability when compared to parental MCF-10A cells
Summary
Adhesion to extracellular matrix (ECM) provides epithelial cells with critical cues about their environment that are required for their proliferation, survival and tissue organization. Most tumor cells have acquired the ability to resist anoikis and this property is believed to be critical for tumor cell dissemination and survival in altered matrix environments [1], [2]. Tumor cells adopt several different strategies to evade anoikis including: (1) activation of survival pathways such as those regulated by Erk/MAPK and Akt through oncogenic mutations or constitutive growth factor receptor activation; (2) modulation of expression or activity of anti-apoptotic and pro-apoptotic proteins including Bcl family members, and (3) altered expression and engagement of integrins by basement membrane proteins produced via autocrine mechanisms (reviewed in [1], [2]). Proteins that are required for anchorage-independent survival of tumor cells represent attractive targets for therapeutic intervention since this property is believed to be critical for survival of tumor cells displaced from their natural niches. We aimed to identify molecules that critically regulate IGF-1-induced anchorage-independent survival
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