Suppression of cancer cell migration and invasion by protein phosphatase 2A through dephosphorylation of mu- and m-calpains

The mu- and m-calpains are major members of the calpain family that play an essential role in regulating cell motility. We have recently discovered that nicotine-activated protein kinase C iota enhances calpain phosphorylation in association with enhanced calpain activity and accelerated migration and invasion of human lung cancer cells. Here we found that specific disruption of protein phosphatase 2A (PP2A) activity by expression of SV40 small tumor antigen up-regulates phosphorylation of mu- and m-calpains whereas C2-ceramide, a potent PP2A activator, reduces nicotine-induced calpain phosphorylation, suggesting that PP2A may function as a physiological calpain phosphatase. PP2A co-localizes and interacts with mu- and m-calpains. Purified, active PP2A directly dephosphorylates mu- and m-calpains in vitro. Overexpression of the PP2A catalytic subunit (PP2A/C) suppresses nicotine-stimulated phosphorylation of mu- and m-calpains, which is associated with inhibition of calpain activity, wound healing, cell migration, and invasion. By contrast, depletion of PP2A/C by RNA interference enhances calpain phosphorylation, calpain activity, cell migration, and invasion. Importantly, C2-ceramide-induced suppression of calpain phosphorylation results in decreased secretion of mu- and m-calpains from lung cancer cells into culture medium, which may have potential clinic relevance in controlling metastasis of lung cancer. These findings reveal a novel role for PP2A as a physiological calpain phosphatase that not only directly dephosphorylates but also inactivates mu- and m-calpains, leading to suppression of migration and invasion of human lung cancer cells.     

Regulation of the Src-PP2A Interaction in Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL)-induced Apoptosis

TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in transformed and tumor cells but not in normal cells, making it a promising agent for cancer therapy. However, many cancer cells are resistant to TRAIL, and the underlying mechanisms are not fully understood. Here, we show that the regulation of the PP2A and Src interaction plays a critical role in TRAIL resistance. Specifically, we show that TRAIL treatment activates the tyrosine kinase Src, which subsequently phosphorylates caspase-8 at tyrosine 380, leading to the inhibition of caspase-8 activation. We also show that upon TRAIL treatment, Src, caspase-8, and PP2A/C (a catalytic subunit of the PP2A phosphatase) are redistributed into lipid rafts, a microdomain of the plasma membrane enriched with cholesterol, where PP2A dephosphorylates Src at tyrosine 418 and in turn inhibits caspase-8 phosphorylation. Furthermore, we find that TRAIL treatment causes PP2A/C degradation. These data suggest that the balance between Src-mediated caspase-8 phosphorylation and the inactivation of Src-mediated caspase-8 phosphorylation by PP2A determines the outcome of TRAIL treatment in breast cancer cells. Therefore, this work identifies a novel mechanism by which the interaction between PP2A and Src in the context of caspase-8 activation modulates TRAIL sensitivity in cancer cells.     

Oncoprotein CIP2A is stabilized via interaction with tumor suppressor PP2A/B56

Protein phosphatase 2A (PP2A) is a critical human tumor suppressor. Cancerous inhibitor of PP2A (CIP2A) supports the activity of several critical cancer drivers (Akt, MYC, E2F1) and promotes malignancy in most cancer types via PP2A inhibition. However, the 3D structure of CIP2A has not been solved, and it remains enigmatic how it interacts with PP2A. Here, we show by yeast two‐hybrid assays, and subsequent validation experiments, that CIP2A forms homodimers. The homodimerization of CIP2A is confirmed by solving the crystal structure of an N‐terminal CIP2A fragment (amino acids 1–560) at 3.0 Å resolution, and by subsequent structure‐based mutational analyses of the dimerization interface. We further describe that the CIP2A dimer interacts with the PP2A subunits B56α and B56γ. CIP2A binds to the B56 proteins via a conserved N‐terminal region, and dimerization promotes B56 binding. Intriguingly, inhibition of either CIP2A dimerization or B56α/γ expression destabilizes CIP2A, indicating opportunities for controlled degradation. These results provide the first structure–function analysis of the interaction of CIP2A with PP2A/B56 and have direct implications for its targeting in cancer therapy.     

Cdc55p-mediated E4orf4 growth inhibition in Saccharomyces cerevisiae is mediated only in part via the catalytic subunit of protein phosphatase 2A

The adenovirus early region 4 open reading frame 4 (E4orf4) protein specifically induces p53-independent cell death of transformed but not normal human cells, suggesting that elucidation of its mechanism may provide important new avenues for cancer therapy. Wild-type E4orf4 and mutants that retain cancer cell toxicity also induce growth inhibition in Saccharomyces cerevisiae, which provides a genetically tractable system for studying E4orf4 function. Interaction with the protein phosphatase 2A (PP2A) B regulatory subunit is required for E4orf4's effects, suggesting that E4orf4 may function by regulating B subunit-containing heterotrimeric PP2A holoenzymes (PP2A(BAC)), which consist of a B subunit complexed with the PP2A structural (A) and catalytic (C) subunits. However, it is not known whether E4orf4-induced growth inhibition requires interaction with the PP2A C subunit or whether E4orf4 might have PP2A B subunit-dependent effects that are independent of PP2A(BAC) holoenzyme formation. To test these possibilities in S. cerevisiae, we disrupted the stable formation of PP2A(BAC) heterotrimers and thus E4orf4/C subunit association by PP2A C subunit point mutations or by deletion of the gene for the PP2A methyltransferase, Ppm1p, and assayed for effects on E4orf4-induced growth inhibition. Our results support a model in which E4orf4 mediates growth inhibition and cell killing both through PP2A(BAC) heterotrimers and through a B regulatory subunit-dependent pathway(s) that is independent of stable complex formation with the PP2A C subunit. They also indicate that Ppm1p has a function other than regulating the assembly of PP2A heterotrimers and suggest that selective PP2A trimer inhibitors and PP6 inhibitors may be useful as adjuvant anticancer therapies.     

The Antihelmintic Drug Pyrvinium Pamoate Targets Aggressive Breast Cancer

WNT signaling plays a key role in the self-renewal of tumor initiation cells (TICs). In this study, we used pyrvinium pamoate (PP), an FDA-approved antihelmintic drug that inhibits WNT signaling, to test whether pharmacologic inhibition of WNT signaling can specifically target TICs of aggressive breast cancer cells. SUM-149, an inflammatory breast cancer cell line, and SUM-159, a metaplastic basal-type breast cancer cell line, were used in these studies. We found that PP inhibited primary and secondary mammosphere formation of cancer cells at nanomolar concentrations, at least 10 times less than the dose needed to have a toxic effect on cancer cells. A comparable mammosphere formation IC50 dose to that observed in cancer cell lines was obtained using malignant pleural effusion samples from patients with IBC. A decrease in activity of the TIC surrogate aldehyde dehydrogenase was observed in PP-treated cells, and inhibition of WNT signaling by PP was associated with down-regulation of a panel of markers associated with epithelial-mesenchymal transition. In vivo, intratumoral injection was associated with tumor necrosis, and intraperitoneal injection into mice with tumor xenografts caused significant tumor growth delay and a trend toward decreased lung metastasis. In in vitro mammosphere-based and monolayer-based clonogenic assays, we found that PP radiosensitized cells in monolayer culture but not mammosphere culture. These findings suggest WNT signaling inhibition may be a feasible strategy for targeting aggressive breast cancer. Investigation and modification of the bioavailability and toxicity profile of systemic PP are warranted.     

Protein phosphatase 2A, a negative regulator of the ERK signaling pathway, is activated by tyrosine phosphorylation of putative HLA class II-associated protein I (PHAPI)/pp32 in response to the antiproliferative lectin, jacalin

Protein phosphatase 2A (PP2A) is a family of mammalian serine/threonine phosphatases that is involved in the control of many cellular functions including those mediated by extracellular signal-regulated kinase (ERK) signaling. While investigating the reversible antiproliferative effect of the dietary lectin, jacalin, which binds the Thomsen-Friedenreich antigen (galactose beta1-3 N-acetylgalactosamine alpha-), we have found that this lectin (30 microg/ml) induces rapid, transient, tyrosine phosphorylation of putative human HLA-DR-associated protein I (PHAPI, also known as the tumor suppressor pp32) in HT29 human colon cancer cells. This is accompanied by the release of PP2A from association with PHAPI, allowing increased phosphatase activity of PP2A (by 42 +/- 10% at 10 min) and consequent complete dephosphorylation of the ERK kinase, MEK1/2, by 10 min and of ERK1/2 by 60 min. PHAPI knockdown by RNA interference abolished the effects of jacalin on PP2A activation and MEK inhibition. Thus phosphorylation of PHAPI/pp32 is a critical regulatory step in PP2A activation and ERK signaling.     

Protein phosphatase 2A mediates dormancy of glioblastoma multiforme-derived tumor stem-like cells during hypoxia

Purpose

The hypoxic microenvironment of glioblastoma multiforme (GBM) is thought to increase resistance to cancer therapies. Recent evidence suggests that hypoxia induces protein phosphatase 2A (PP2A), a regulator of cell cycle and cell death. The effects of PP2A on GBM tumor cell proliferation and survival during hypoxic conditions have not been studied.

Experimental Design

Expression of PP2A subunits and HIF-α proteins was measured in 65 high-grade astrocytoma and 18 non-neoplastic surgical brain specimens by western blotting. PP2A activity was measured by an immunoprecipitation assay. For in vitro experiments, GBM-derived tumor stem cell-like cells (TSCs) were exposed to severe hypoxia produced by either CoCl₂ or 1% O₂. PP2A activity was inhibited either by okadaic acid or by shRNA depletion of the PP2A C subunit. Effects of PP2A activity on cell cycle progression and cell survival during hypoxic conditions were assessed using flow cytometry.

Results

In our patient cohort, PP2A activity was positively correlated with HIF-1∝ protein expression (P = 0.002). Patients with PP2A activity levels above 160 pMP had significantly worse survival compared to patients with levels below this threshold (P = 0.002). PP2A activity was an independent predictor of survival on multivariable analysis (P = 0.009). In our in vitro experiments, we confirmed that severe hypoxia induces PP2A activity in TSCs 6 hours after onset of exposure. PP2A activity mediated G1/S phase growth inhibition and reduced cellular ATP consumption in hypoxic TSCs. Conversely, inhibition of PP2A activity led to increased cell proliferation, exhaustion of intracellular ATP, and accelerated P53-independent cell death of hypoxic TSCs.

Conclusions

Our results suggest that PP2A activity predicts poor survival in GBM. PP2A appears to reduce the metabolic demand of hypoxic TSCs and enhances tumor cell survival. Modulation of PP2A may be a potential target for cancer therapy.     

SET-mediated NDRG1 inhibition is involved in acquisition of epithelial-to-mesenchymal transition phenotype and cisplatin resistance in human lung cancer cell

Development of resistance to therapy continues to be a serious clinical problem in lung cancer management. Cancer cells undergoing epithelial-to-mesenchymal transition (EMT) have been shown to play roles in resistance to chemotherapy. Here, we utilized a proteomics-based method and identified a significant downregulation of the metastasis suppressor NDRG1 in drug resistant lung cancer cells. We showed that downregulation of DNRG1 constitutes a mechanism for acquisition of EMT phenotype and endows lung cancer cells with an increased resistance to cisplatin. We also identified a signal cascade, namely, SET---| PP2A---| c-myc---| NDRG1, in which upregulation of SET is critical for inhibition of NDRG1. We also found that blockade of SET (or reactivation of PP2A) by FTY720 reverted EMT, restored drug sensitivity, and inhibited invasiveness and growth of lung tumor xenografts. Together, our results indicated a functional link between SET-mediated NDRG1 regulation and acquisition of EMT phenotype and drug resistance, and provided an evidence that blockade of SET-driven EMT can overcome drug resistance and inhibit tumor progression.     

Mouse model for probing tumor suppressor activity of protein phosphatase 2A in diverse signaling pathways

Evidence that protein phosphatase 2A (PP2A) is a tumor suppressor in humans came from the discovery of mutations in the genes encoding the Aα and Aβ subunits of the PP2A trimeric holoenzymes, Aα-B-C and Aβ-B-C. One point mutation, Aα-E64D, was found in a human lung carcinoma. It renders Aα specifically defective in binding regulatory B’ subunits. Recently, we reported a knock-in mouse expressing Aα-E64D and an Aα knockout mouse. The mutant mice showed a 50–60% increase in the incidence of lung cancer induced by benzopyrene. Importantly, PP2A’s tumor suppressor activity depended on p53. These data provide the first direct evidence that PP2A is a tumor suppressor in mice. In addition, they suggest that PP2A is a tumor suppressor in humans. Here, we report that PP2A functions as a tumor suppressor in mice that develop lung cancer triggered by oncogenic K-ras. We discuss whether PP2A may function as a tumor suppressor in diverse tissues, with emphasis on endometrial and ovarian carcinomas, in which Aα mutations were detected at a high frequency. We propose suitable mouse models for examining whether PP2A functions as tumor suppressor in major growth-stimulatory signaling pathways, and we discuss the prospect of using the PP2A activator FTY720 as a drug against malignancies that are driven by these pathways.     

Induction of cancer cell apoptosis by alpha-tocopheryl succinate: molecular pathways and structural requirements.

The vitamin E analog alpha-tocopheryl succinate (alpha-TOS) can induce apoptosis. We show that the proapoptotic activity of alpha-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented alpha-TOS-triggered apoptosis. More selective effectors indicated that alpha-TOS reduced PKCalpha isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCalpha inhibition in alpha-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCalpha overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of alpha-TOS-induced proapoptotic signals. Structural analogs revealed that alpha-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, alpha-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.     

Retroviral cyclin enhances cyclin-dependent kinase-8 activity

Alterations in the functional levels of cyclin-dependent kinase-8 (CDK8) or its partner, cyclin C, have been clearly associated with cancers, including colon cancer, melanoma, and osteosarcoma. Walleye dermal sarcoma virus encodes a retroviral cyclin (RV-cyclin) that localizes to interchromatin granule clusters and binds CDK8. It also binds to the Aα subunit (PR65) of protein phosphatase 2A (PP2A). Binding to the Aα subunit excludes the regulatory B subunit, but not the catalytic C subunit, in a manner similar to that of T antigens of the small DNA tumor viruses. The expression of the RV-cyclin enhances the activity of immune affinity-purified CDK8 in vitro for RNA polymerase II carboxy-terminal domain (CTD) and histone H3 substrates. PP2A also enhances CDK8 kinase activity in vitro for the CTD but not for histone H3. The PP2A enhancement of CDK8 is independent of RV-cyclin expression and likely plays a role in the normal regulation of CDK8. The manipulation of endogenous PP2A activity by inhibition, amendment, or depletion confirmed its role in CDK8 activation by triggering CDK8 autophosphorylation. Although RV-cyclin and PP2A both enhance CDK8 activity, their actions are uncoupled and additive in kinase reactions. PP2A may be recruited to CDK8 in the Mediator complex by a specific PP2A B subunit or additionally by the RV-cyclin in infected cells, but the RV-cyclin appears to activate CDK8 directly and in a manner independent of its physical association with PP2A.     

PP2A通过Akt/Skp2通路调控p27~(Kip1)的表达并抑制肺癌细胞的致瘤能力

蛋白磷酸酶2A(PP2A)是由36 k Da的催化亚基C(PP2Ac)和65 k Da的结构亚基A(PP2Aα/β)一起组成PP2A的核心酶,并且和各种不同的调节亚基B形成具有不同功能的PP2A全酶复合体。在细胞中PP2A发挥着重要作用,特别是在抑制肿瘤的形成当中,编码PP2Aα/β基因的突变将导致肿瘤的形成和其他疾病。当非小细胞肺癌细胞H1299中过表达PP2A-Aα时,细胞生长被抑制,细胞周期停留在G0/G1期,致瘤能力也同时被抑制。进一步研究证明当PP2A-Aα过表达时,Akt被去磷酸化失活使Skp2的表达下调,从而导致细胞周期抑制因子p27kip1的表达上调。肿瘤细胞软琼脂克隆形成实验的结果表明过表达PP2A-Aα之后H1299细胞的锚定非依赖性生长能力明显的降低,形成的克隆细胞团也较小,这些结果和裸鼠成瘤实验的结果是一致的。     

含B56调节亚基的PP2A全酶在肿瘤信号通路中的调控作用

蛋白磷酸酶2A（protein phosphatase 2A,PP2A）是细胞中广泛表达的异三聚体全酶,调节许多重要的信号通路,它的表达异常所致的信号通路紊乱会引发肿瘤和促进肿瘤的发展.PP2A在特定的状态下能够发挥抑癌因子的作用,这种抑癌特性由B调节亚基与底物的相互作用来决定,因此B调节亚基在PP2A的抑癌功能中起关键作用.     

The role of Cullin3-mediated ubiquitination of the catalytic subunit of PP2A in TRAIL signaling

Protein phosphatase 2A (PP2A) is the major serine-threonine phosphatase that regulates a number of cell signaling pathways. PP2A activity is controlled partially through protein degradation; however, the underlying mechanism is not fully understood. Here we show that PP2A/C, a catalytic subunit of PP2A, is degraded by the Cullin3 (Cul3) ligase-mediated ubiquitin-proteasome pathway. In response to death receptor signaling by tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL), PP2A/C, caspase-8 and Cul3, a subunit of the cullin family of E3 ligases, are recruited into the death-inducing signaling complex (DISC) where the Cul3 ligase targets PP2A/C for ubiquitination and subsequent degradation. Functionally, knockdown of PP2A/C expression by siRNA or pharmacological inhibition of PP2A activity increases TRAIL-induced apoptosis. In cancer cells that have developed acquired TRAIL resistance, PP2A phosphatase activity is increased, and PP2A/C protein is resistant to TRAIL-induced degradation. Thus, this work identifies a new mechanism by which PP2A/C is regulated by Cul3 ligase-mediated degradation in response to death receptor signaling and suggests that inhibition of PP2A/C degradation may contribute to resistance of cancer cells to death receptor-induced apoptosis.     

Hyperphosphorylation of PP2A in colorectal cancer and the potential therapeutic value showed by its forskolin-induced dephosphorylation and activation

BackgroundThe tumor suppressor protein phosphatase 2A (PP2A) is frequently inactivated in human cancer and phosphorylation of its catalytic subunit (p-PP2A-C) at tyrosine-307 (Y307) has been described to inhibit this phosphatase. However, its molecular and clinical relevance in colorectal cancer (CRC) remains unclear.Methodsp-PP2A-C Y307 was determined by immunoblotting in 7 CRC cell lines and 35 CRC patients. CRC cells were treated with the PP2A activator forskolin alone or combined with the PP2A inhibitor okadaic acid, 5-fluorouracil and oxaliplatin. We examined cell growth, colonosphere formation, caspase activity and AKT and ERK activation.ResultsPP2A-C was found hyperphosphorylated in CRC cell lines. Forskolin dephosphorylated and activated PP2A, impairing proliferation and colonosphere formation, and inducing activation of caspase 3/7 and changes in AKT and ERK phosphorylation. Moreover, forskolin showed additive effects with 5-fluorouracil and oxaliplatin treatments. Analysis of p-PP2A-C Y307 in primary tumors confirmed the presence of this alteration in a subgroup of CRC patients.ConclusionsOur data show that PP2A-C hyperphosphorylation is a frequent event that contributes to PP2A inhibition in CRC. Antitumoral effects of forskolin-mediated PP2A activation suggest that the analysis of p-PP2A-C Y307 status could be used to identify a subgroup of patients who would benefit from treatments based on PP2A activators.     

Human cancer-associated mutations in the Aα subunit of protein phosphatase 2A increase lung cancer incidence in Aα knock-in and knockout mice

Strong evidence has indicated that protein phosphatase 2A (PP2A) is a tumor suppressor, but a mouse model for testing the tumor suppressor activity was missing. The most abundant forms of trimeric PP2A holoenzyme consist of the scaffolding Aα subunit, one of several regulatory B subunits, and the catalytic Cα subunit. Aα mutations were discovered in a variety of human carcinomas. All carcinoma-associated mutant Aα subunits are defective in binding the B or B and C subunits. Here we describe two knock-in mice expressing cancer-associated Aα point mutants defective in binding B' subunits, one knockout mouse expressing truncated Aα defective in B and C subunit binding, and a floxed mouse for generating conditional Aα knockouts. We found that the cancer-associated Aα mutations increased the incidence of cancer by 50 to 60% in lungs of FVB mice treated with benzopyrene, demonstrating that PP2A acts as a tumor suppressor. We show that the effect of Aα mutation on cancer incidence is dependent on the tumor suppressor p53. The finding that the Aα mutation E64D, which was detected in a human lung carcinoma, increases the lung cancer incidence in mice suggests that this mutation also played a role in the development of the carcinoma in which it was discovered.     

A Src family inhibitor (PP1) potentiates tumor-suppressive effect of connexin 32 gene in renal cancer cells

Connexin (Cx) genes exert negative growth effects on tumor cells with certain cell specificity. We have recently reported that Cx32 acts as a tumor suppressor gene in renal cancer cells due to the inhibition of Src-dependent signaling. In line with the previous study, here we examined if a Src family inhibitor (PP1) could potentiate tumor-suppressive effect of Cx32 in Caki-2 cell from human renal cell carcinoma. In order to clarify the potentialization of PP1, using Cx32-transfected Caki-2 cells and mock-transfected Caki-2 cells, we estimated difference in cytotoxic effect of PP1 on the two cell clones in vitro as well as in vivo. PP1 showed more cytotoxic effect on Caki-2 cells having Cx32 positive expression than that of Cx32 negative expression at lower doses. This potentialization was also observed in xenograft model of nude mice. The potentialization of the effect mainly depended on the induction of apoptosis but not the control of cell growth. In conjugation with this event, the reduction of anti-apoptotic molecules (Bcl-2 and Bcl-xL) was caused by the combination of Cx32 expression and PP1 treatment in Caki-2 cells. These results suggest that PP1 potentiates tumor-suppressive effect of connexin 32 gene in renal cancer cells through the reduction of anti-apoptotic molecules.     

Protein Phosphatase Methyl-Esterase PME-1 Protects Protein Phosphatase 2A from Ubiquitin/Proteasome Degradation

Protein phosphatase 2A (PP2A) is a conserved essential enzyme that is implicated as a tumor suppressor based on its central role in phosphorylation-dependent signaling pathways. Protein phosphatase methyl esterase (PME-1) catalyzes specifically the demethylation of the C-terminal Leu309 residue of PP2A catalytic subunit (PP2Ac). It has been shown that PME-1 affects the activity of PP2A by demethylating PP2Ac, but also by directly binding to the phosphatase active site, suggesting loss of PME-1 in cells would enhance PP2A activity. However, here we show that PME-1 knockout mouse embryonic fibroblasts (MEFs) exhibit lower PP2A activity than wild type MEFs. Loss of PME-1 enhanced poly-ubiquitination of PP2Ac and shortened the half-life of PP2Ac protein resulting in reduced PP2Ac levels. Chemical inhibition of PME-1 and rescue experiments with wild type and mutated PME-1 revealed methyl-esterase activity was necessary to maintain PP2Ac protein levels. Our data demonstrate that PME-1 methyl-esterase activity protects PP2Ac from ubiquitin/proteasome degradation.     

新基因BCAPP2Ac在膀胱癌中的表达 及其对膀胱癌细胞增殖的影响

为探讨膀胱癌相关蛋白磷酸酶2A催化亚单位（BCAPP2Ac）新基因在膀胱癌组织中的表达及其对膀胱癌细胞增殖的影响,通过合成抗原多肽免疫家兔获得抗BCAPP2Ac多克隆抗体及通过慢病毒感染方式获得稳定表达BCAPP2Ac的膀胱癌细胞.采用实时PCR及免疫组化染色方法检测BCAPP2Ac mRNA和蛋白在膀胱癌组织、癌旁组织及其它多种肿瘤组织中的表达;用细胞增殖实验检测BCAPP2Ac对膀胱癌细胞增殖的影响.实时PCR及免疫组化结果显示,BCAPP2Ac mRNA及蛋白在膀胱癌组织较癌旁组织表达明显下调;过表达BCAPP2Ac能抑制膀胱癌EJ、T24细胞的增殖, 蛋白磷酸酶2A催化结构域缺失（△PP2Ac）能逆转BCAPP2Ac的增殖抑制作用.研究结果提示,新基因BCAPP2Ac能抑制膀胱癌细胞的增殖,PP2Ac结构域在其抑制细胞增殖作用中发挥重要作用.