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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Shank-interacting protein-like 1 promotes tumorigenesis via PTEN inhibition in human tumor cells
Lizhi He1, Alistair Ingram, Adrian P Rybak
1Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Abstract:
Inactivation of phosphatase and tensin homolog (PTEN) is a critical step during tumorigenesis, and PTEN inactivation by genetic and epigenetic means has been well studied. There is also evidence suggesting that PTEN negative regulators (PTEN-NRs) have a role in PTEN inactivation during tumorigenesis, but their identity has remained elusive. Here we have identified shank-interacting protein-like 1 (SIPL1) as a PTEN-NR in human tumor cell lines and human primary cervical cancer cells. Ectopic SIPL1 expression protected human U87 glioma cells from PTEN-mediated growth inhibition and promoted the formation of HeLa cell-derived xenograft tumors in immunocompromised mice. Conversely, siRNA-mediated knockdown of SIPL1 expression inhibited the growth of both HeLa cells and DU145 human prostate carcinoma cells in vitro and in vivo in a xenograft tumor model. These inhibitions were reversed by concomitant knockdown of PTEN, demonstrating that SIPL1 affects tumorigenesis via inhibition of PTEN function. Mechanistically, SIPL1 was found to interact with PTEN through its ubiquitin-like domain (UBL), inhibiting the phosphatidylinositol 3,4,5-trisphosphate (PIP3) phosphatase activity of PTEN. Furthermore, SIPL1 expression correlated with loss of PTEN function in PTEN-positive human primary cervical cancer tissue. Taken together, these observations indicate that SIPL1 is a PTEN-NR and that it facilitates tumorigenesis, at least in part, through its PTEN inhibitory function.
Insights
Shank-interacting protein-like 1 (SIPL1) acts as a negative regulator of phosphatase and tensin homolog (PTEN). SIPL1 promotes tumor growth by inhibiting PTEN function, identifying it as a potential therapeutic target in cancer.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Phosphatase and tensin homolog (PTEN) inactivation is crucial in tumorigenesis.
- PTEN negative regulators (PTEN-NRs) are implicated in PTEN inactivation, but their identities are largely unknown.
- Understanding PTEN-NRs is vital for developing targeted cancer therapies.
Purpose of the Study:
- To identify novel PTEN negative regulators (PTEN-NRs) involved in tumorigenesis.
- To elucidate the mechanism by which SIPL1 regulates PTEN activity.
- To investigate the role of SIPL1 in various human cancers.
Main Methods:
- Identified shank-interacting protein-like 1 (SIPL1) as a PTEN-NR in human tumor cell lines and primary cervical cancer cells.
- Assessed the impact of ectopic SIPL1 expression and SIPL1 knockdown on cell growth and tumor formation in vitro and in vivo xenograft models.
- Investigated the interaction between SIPL1 and PTEN using biochemical assays and analyzed SIPL1 expression in patient tissues.
Main Results:
- Ectopic SIPL1 expression promoted tumor growth and protected cells from PTEN-mediated inhibition.
- SIPL1 knockdown inhibited tumor growth, an effect reversed by concomitant PTEN knockdown.
- SIPL1 interacts with PTEN via its ubiquitin-like domain (UBL), inhibiting PTEN's PIP3 phosphatase activity and correlating with PTEN loss in cervical cancer.
Conclusions:
- Shank-interacting protein-like 1 (SIPL1) is identified as a novel PTEN negative regulator.
- SIPL1 facilitates tumorigenesis by inhibiting PTEN function, representing a potential therapeutic target.
- These findings highlight SIPL1 as a key player in PTEN regulation and cancer development.
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