Abstract
Many tumors present with increased activation of the phosphatidylinositol 3-kinase (PI3K)-PtdIns(3,4,5)P(3)-protein kinase B (PKB/Akt) signaling pathway. It has long been thought that the lipid phosphatases SH2 domain-containing inositol-5'-phosphatase 1 (SHIP1) and SHIP2 act as tumor suppressors by counteracting with the survival signal induced by this pathway through hydrolysis or PtdIns(3,4,5)P(3) to PtdIns(3,4)P(2). However, a growing body of evidence suggests that PtdInd(3,4)P(2) is capable of, and essential for, Akt activation, thus suggesting a potential role for SHIP1/2 enzymes as proto-oncogenes. We recently described a novel SHIP1-selective chemical inhibitor (3α-aminocholestane [3AC]) that is capable of killing malignant hematologic cells. In this study, we further investigate the biochemical consequences of 3AC treatment in multiple myeloma (MM) and demonstrate that SHIP1 inhibition arrests MM cell lines in either G0/G1 or G2/M stages of the cell cycle, leading to caspase activation and apoptosis. In addition, we show that in vivo growth of MM cells is blocked by treatment of mice with the SHIP1 inhibitor 3AC. Furthermore, we identify three novel pan-SHIP1/2 inhibitors that efficiently kill MM cells through G2/M arrest, caspase activation and apoptosis induction. Interestingly, in SHIP2-expressing breast cancer cells that lack SHIP1 expression, pan-SHIP1/2 inhibition also reduces viable cell numbers, which can be rescued by addition of exogenous PtdIns(3,4)P(2). In conclusion, this study shows that inhibition of SHIP1 and SHIP2 may have broad clinical application in the treatment of multiple tumor types.
Highlights
Inositol phospholipids play a crucial role in all aspects of cell biology, from cell survival, differentiation and migration, to immune function, organ development and tumor growth
Activation of SH2 domain-containing inositol-5′-phosphatase 1 (SHIP1) has been shown to have antitumorigenic effects in MM cells. Because both the SHIP substrate PtdIns(3,4,5)P3 and its product PtdIns(3,4)P2 are capable of activating the Akt survival pathway in MM cells (Figure 1A), it is conceivable that inhibition of SHIP1 may lead to cell death
Because MM is a heterogeneous disease, we tested whether other SHIP1-expressing MM cell lines would be affected
Summary
Inositol phospholipids play a crucial role in all aspects of cell biology, from cell survival, differentiation and migration, to immune function, organ development and tumor growth. Their production is carefully regulated by a wide range of lipid kinases and phosphatases (1,2). Many tumors, including breast cancer and hematological malignancies such as the plasma cell neoplasm multiple myeloma (MM), present with constitutive activation of the PI3K-Akt pathway (3). Activating mutations in the PI3K gene (PIK3CA) have been described, but constitutive PI3K signaling may occur as a secondary effect (4). Activating mutations in receptor tyrosine kinases or Ras, oncogenic translocation products, and cytokine signaling loops have been described as contributing factors (5,6). Regardless of the activating mechanism, targeting the PI3K/Akt pathway with specific inhibitors is believed to be a promising approach in treating cancer (7,8)
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