Inositol Polyphosphate 4-Phosphatase Type II Is a Tumor Suppressor in Multiple Myeloma

Abstract

Inositol polyphosphate-4-phosphatase type II (INPP4B) has been identified as a tumor suppressor, while little is known about its expression and function in multiple myeloma (MM). In this study, we evaluated the expression of INPP4B in 28 cases of newly diagnosed MM patients and 42 cases of extramedullary plasmacytoma (EMP) patients compared with normal plasma cells and found that low INPP4B expression was correlated with poor outcomes in MM patients. Moreover, expression of INPP4B in seven MM cell lines was all lower than that in normal plasma cells. In addition, loss of function of INPP4B promoted cell proliferation in MM cells; however, gain of function suppressed MM cells proliferation and arrested the cell cycle at G0/G1 phage. Meanwhile, knockdown of INPP4B enhanced resistance, but overexpression promoted sensitivity to bortezomib treatment in MM cells. Mechanistically, we found that INPP4B exerted its role via inhibiting the phosphorylation of Akt at lysine 473 but not threonine 308, which attenuated the activation of the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway. Therefore, we identified an inhibitory effect of INPP4B in MM, and our findings suggested that loss of INPP4B expression is a risk factor of aggressive MM.

Tumor Suppressor Role of INPP4B in Chemoresistant Retinoblastoma

“…In the study presented, INPP4B overexpression reduced proliferation, viability, and growth of etoposide-resistant RB cell lines and concomitantly increased caspase-3/7 mediated apoptosis levels, supporting INPP4B`s role as a tumor suppressor in RB cells. Consistent with our data, it has been demonstrated that INPP4B overexpression inhibits cervical and human hepatocellular carcinoma (HCC) as well as multiple myeloma and acute myeloid leukemia, cell proliferation, and induces caspase-3-mediated apoptosis in HCC cell lines [ 10 , 21 , 31 ]. Similarly, INPP4B knockdown increased the proliferation of human basal-like breast cancer cells [ 26 ].…”

“…INPP4B levels are significantly reduced in human hepatocellular, gastric, and gallbladder carcinoma [ 10 , 28 , 29 ]. In a most recent study, decreased INPP4B expression levels were reported for multiple myeloma cell lines as well as bone marrow plasma of multiple myeloma patients, and lower INPP4B levels correlated with a poor outcome [ 31 ]. Fittingly, in the study presented, we demonstrated that compared to the healthy human retina INPP4B mRNA expression levels are significantly decreased in RB cell lines, indicating a tumor-suppressing role of INPP4B in retinoblastoma.…”

“…It has been demonstrated that overexpression of INPP4B induces chemosensitivity in human hepatocellular carcinoma and prostate cancer cells lines [ 10 , 50 ]. Wang et al likewise demonstrated that INPP4B overexpressing multiple myeloma cells become more sensitive to bortezomib, while INPP4B knockdown cells became more resistant to bortezomib treatment strongly suggesting INPP4B as a key regulator of chemosensitivity [ 31 ]. Accordingly, INPP4B overexpression inhibited chemoresistance of primary nonmetastatic CR-CSLCs, but increased chemosensitivity in metastatic CR-CSLCs [ 49 ].…”

“…INPP4B has been reported as a negative regulator of PI3K/AKT signaling [ 13 ] and was anticipated to act as a tumor suppressor by inhibiting this pathway [ 27 ]. Most recently, Wang et al demonstrated that INPP4B overexpression decreased the phosphorylation of AKT in multiple myeloma and hepatocellular carcinoma cells [ 31 ], whereas tumors derived from INPP4B knockout mice were found to be enriched for AKT [ 25 ]. It has, however, been shown that in cervical carcinoma cells INPP4B overexpression reduces the phosphorylation of both AKT and SGK3, sharing structural and functional similarities [ 21 ].…”

“…INPP4B knockout (Inpp4b −/− ) mice are viable and have a normal lifespan but develop defects in bone homeostasis at 8 weeks of age [23]. As INPP4B levels are signifcantly decreased in various cancers, it has frst been described as a tumor suppressor gene, e.g., in prostate, basallike breast, ovarian, cervical, gallbladder, and gastric cancer [21,[24][25][26][27][28][29], as well as thyroid neoplasm [30] and multiple myeloma [31]. However, several studies have reported an increased INPP4B expression, e.g., in AML, colon cancer, and a subset of melanomas [32][33][34] revealing the paradoxical role of an oncogene [17,35].…”