Expression of PTEN in PTEN-deficient multiple myeloma cells abolishes tumor growth in vivo

Abstract

Biochemical abnormalities associated with the development of multiple myeloma have been di cult to de®ne especially in terms of demonstrating an in vivo e ect of suspected lesions. Herein, we have identi®ed such a defect associated with lack of expression of PTEN, a cellular phosphatase involved in the regulation of phosphatidylinositol phosphates (PIP's). In myeloma cells, PIP's are required for phosphorylation of Akt, a key event leading to inhibition of apoptosis. Loss of PTEN results in a failure to de-phosphorylate PIP's and a corresponding increase in Akt phosphorylation. OPM-2 cells lacking PTEN expression have the highest level of Akt phosphorylation of eight lines examined. Loss of PTEN was found to be associated with a 630 bp deletion corresponding to amino acids 56 ± 267. Ectopic expression of wild type PTEN in OPM-2 cells inhibited Akt phosphorylation which was correlated with an increase in apoptosis. The in vivo relevance of loss of PTEN expression was demonstrated by injecting control and wild type PTEN transfected OPM-2 cells into SCID mice. Tumors arose at an incidence of 100% in controls, but only 50% (and of smaller size and longer latency) in low PTEN expressing clones. Importantly, clones expressing high levels of PTEN failed to produce tumors even at ®ve times the latency period of controls. These results demonstrate that PTEN deletion/mutation is responsible for in vivo growth of this tumor and suggests that PTEN regulation may play an important role in tumor development in a subset of multiple myeloma patients. Oncogene (2000) 19, 4091 ± 4095.

Insulinlike growth factor–I signaling in multiple myeloma: downstream elements, functional correlates, and pathway cross-talk

“…Several elements of the PI-3K pathway, including the PTEN tumor suppressor gene, Akt kinase, and Bad, have been demonstrated to affect myeloma cell growth both in vitro and in vivo. 17 However, additional elements downstream in these cascades and their functions in either proliferation or apoptosis have yet to be defined. Here, we have described experiments in which a number of downstream targets have been identified and functional correlates established for both MAPK and PI-3K pathways.…”

“…Also, regulation of Akt phosphorylation by the PTEN tumor suppressor gene is critical in tumor cell proliferation, as in vivo growth of a myeloma line lacking PTEN can be prevented by expression of normal PTEN protein following gene transfection. 17 The second pathway associated with IGF-I stimulation signals through the Shc, Grb-2, Sos complex, resulting in activation of Ras and subsequently the mitogen-activated protein kinase (MAPK) signaling cascade. Whereas at least part of the effect of the PI-3K pathway has been demonstrated to be associated with apoptosis, the role of additional members of this cascade, as well as those in the MAPK pathway, has, in terms of proliferation or apoptosis, not been defined in myeloma cells.…”

Thalidomide decreases gelatinase production by malignant B lymphoid cell lines through disruption of multiple integrin-mediated signaling pathways

“…PTEN is a lipid phosphatase that dephosphorylates PIP3, decreasing Akt activation. [28][29][30] PTEN is considered to be a tumor suppressor gene given that loss of PTEN activity, as a result of deletion or mutation of the gene, is commonly found in solid tumors. However, although PTEN mutations can be found in some cases of MM, 28 loss of PTEN function is an uncommon pathway of malignant transformation in lymphoproliferative disorders.…”

“…[28][29][30] PTEN is considered to be a tumor suppressor gene given that loss of PTEN activity, as a result of deletion or mutation of the gene, is commonly found in solid tumors. However, although PTEN mutations can be found in some cases of MM, 28 loss of PTEN function is an uncommon pathway of malignant transformation in lymphoproliferative disorders. 6,31 We found that thalidomide reduced fibronectin-induced PTEN phosphorylation in IM9 cells PTEN activation, which may reduce even more downstream effects of PI3-kinase in IM9 and cells expressing functional PTEN.…”

Genetics and Cytogenetics of Multiple Myeloma

“…Inactivation of PTEN, which negatively regulates the phosphatidylinositol 3-kinase (PI3K)-mediated phosphorylation of AKT and BAD, inhibits apoptosis. Inactivating mutations of PTEN were identified in two of eight HMCLs, and transfection of normal PTEN into one of these HMCLs inhibited tumor formation in mice (159,160).…”