The protein phosphatase 2A regulatory subunit B55α is a modulator of signaling and microRNA expression in acute myeloid leukemia cells

Abstract

We recently discovered that the protein phosphatase 2A (PP2A) B55α subunit (PPP2R2A) is under-expressed in primary blast cells and is unfavorable for remission duration in AML patients. In this study, reverse phase protein analysis (RPPA) of 230 proteins in 511 AML patient samples revealed a strong correlation of B55α with a number of proteins including MYC, PKC α, and SRC. B55α suppression in OCI-AML3 cells by shRNA demonstrated that the B subunit is a PKCα phosphatase. B55α does not target SRC, but rather the kinase suppresses protein expression of the B subunit. Finally, the correlation between B55α and MYC levels reflected a complex stoichiometric competition between B subunits. Loss of B55α in OCI-AML3 cells did not change global PP2A activity and the only isoform that is induced is the one containing B56α. In cells containing B55α shRNA, MYC was suppressed with concomitant induction of the competing B subunit B56α (PPP2R5A). A recent study determined that FTY-720, a drug whose action involves the activation of PP2A, resulted in the induction of B55α In AML cells, and a reduction of the B subunit rendered these cells resistant to FTY-720. Finally, reduction of the B subunit resulted in an increase in the expression of miR-191-5p and a suppression of miR-142-3p. B55α regulation of these miRs was intriguing as high levels of miR-191 portend poor survival in AML, and miR-142-3p is mutated in 2% of AML patient samples. In summary, the suppression of B55α activates signaling pathways that could support leukemia cell survival.

MicroRNA‑191‑5p exerts a tumor suppressive role in renal cell carcinoma

“…In addition, miR-191-5p overexpression has been observed in oral squamous cell carcinoma, although it remains unclear how it contributes to the development of this tumor. Furthermore, miR-191-5p is associated with poor prognosis in pancreatic cancer (36), chromophobe RCC (37), acute myeloid leukemia (38), glioblastoma (39) and malignant melanoma (40). In contrast to these previous studies, the present study observed that miR-191-5p was downregulated in RCC tissues and cells.…”

Activation of protein phosphatase 2A in FLT3+ acute myeloid leukemia cells enhances the cytotoxicity of FLT3 tyrosine kinase inhibitors

“…see reviews [18, 51–54]). For example, loss of PP2A-B56α results in accumulation of c-MYC [55], while reduced PP2A-B55α leads to enhanced phosphorylation of AKT [56, 57], both important downstream effectors of FLT3.…”

Proteomic profile of acute myeloid leukaemia: A review update

“…Likewise, the potential mechanism essential to the regulation and expression of B55α, in addition to the likely role of the B subunit as a tumor suppressor in AML were comprehensively studied [30]. A strong correlation was observed between B55α and several proteins (including MYC, PKCα, and SRC) after reverse phase protein analysis (RPPA) of 230 proteins in 511 AML patients.…”

“…The miR-142-3p was mutated in approximately 2 % of AML patients. Conclusively, the suppression of B55α activates signaling pathways that could guarantee the survival of leukaemia cells [30]. The validity of applying the proteomic profiling would require comprehensive verification via clinical trials on mice or by using advanced and sensitive molecular assays such as western plot (WP) or RT-PCR.…”

“…K-562 and HEL cells [20] Study the prognostic role of AKT mediated GSK3 phosphorylation in AML Investigate the proteome analysis of four AML cell lines (NB4, THP1, PLB985, and HL-60) and one CML (K-562) Cell surface biotinylation and mass spectrometric analysis Five human myeloid leukemia cell lines and normal human granulocytes, which was used [27] Study the expression of miRNA profiles of two human AML cell lines (HL-60 and THP-1), and one human CML cell line (K-562) followed by differential expression analysis and target prediction Massively parallel sequencing for an indepth analysis of the miRNomes Three myeloid leukemia cell lines [29] Investigation of the potential mechanism underlying the regulation and expression of B55α, in addition to the possible role for the B subunit as a tumor suppressor in AML RPPA of 230 proteins 511 AML patients [30] Comparison between the efficiency of three high-abundance protein depletion methods This is important given that understanding the molecular mechanisms in treatment responses and disease recurrence is limited in AML. The majority of obtainable biomarkers are single biomolecules with low sensitivity and specificity.…”