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. 2020 Feb 3;19(5):592–600. doi: 10.1080/15384101.2020.1723195

Targeting PP2A inhibits the growth of triple-negative breast cancer cells

Mohammed Hafiz Uddin a,*, Julio M Pimentel a,b,*, Madhumita Chatterjee a, Joshu E Allen c,#, Zhengping Zhuang d, Gen Sheng Wu a,b,✉
PMCID: PMC7100985  PMID: 32011210

ABSTRACT

Triple-negative breast cancer (TNBC) does not respond to widely used targeted/endocrine therapies because of the absence of progesterone and estrogen receptors and HER2 amplification. It has been shown that the majority of TNBC cells are highly sensitive to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, but the development of TRAIL resistance limits its efficacy. We previously found that protein phosphatase 2A (PP2A) plays an important role in TRAIL resistance. In this study, we evaluated the effects of PP2A inhibition on cell death in TRAIL-resistant TNBC cells. We found that the PP2A inhibitor LB-100 effectively inhibits the growth of a panel of TNBC cell lines including lines that are intrinsically resistant to TRAIL. Using two TRAIL-resistant cell lines generated from TRAIL-sensitive parental cells (MDA231 and SUM159), we found that both TRAIL-sensitive and -resistant cell lines are equally sensitive to LB-100. We also found that LB-100 sensitizes TNBC cells to clinically used chemotherapeutical agents, including paclitaxel and cisplatin. Importantly, we found that LB-100 effectively inhibits the growth of MDA468 tumors in mice in vivo without apparent toxicity. Collectively, these data suggest that pharmacological inhibition of PP2A activity could be a novel therapeutic strategy for treating patients with TNBC in a clinical setting.

KEYWORDS: TRAIL, PP2A inhibitor, TNBC, apoptosis

Introduction

Breast cancer is the most common cancer and the second-most common cause of cancer deaths among women in the US [1]. Breast tumors are heterogeneous with at least five distinct types of breast tumors being recognized [2]. One of these subtypes is triple-negative breast cancer (TNBC). Patients with TNBC do not benefit from widely used targeted therapies [3,4] because TNBC lacks the expression of estrogen receptor (ER), progesterone receptor (PR) and HER2 amplification [5,6]. TNBC makes up approximately 15–20% of all breast cancer cases [3,4]. Standard of care for TNBC patients is conventional chemotherapeutic agents, including taxanes and anthracyclines [5], but relapse is inevitable [3]. Therefore, there is an urgent need to develop more effective treatment regimens for patients with TNBC. Despite the lack of targeted therapies, most of the TNBC cells are highly sensitive to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis [7], suggesting that patients with TNBC may benefit from TRAIL-based therapies.

TRAIL (also known as Apo2 ligand) is a cytokine belonging to the TNF superfamily [8,9]. TRAIL selectively induces programmed cell death in transformed and tumor cells without harming normal cells making it an attractive target for cancer therapies [8–10]. TRAIL induces apoptosis through the engagement of its two death receptors DR4 and DR5 [11–15]. When TRAIL binds to DR4 and DR5, it promotes the recruitment of FADD and procaspase 8 to form the death-inducing signaling complex (DISC). Once the DISC is formed, caspase 8 can be activated, which ensures the activation of downstream caspase 3, 6 and 7, leading to apoptotic cell death [16]. Despite the fact that TRAIL selectively induces cancer cell death, the results from TRAIL-based clinical trials are disappointing. The reasons can be multifactorial [17–27], including both primary and acquired resistance [28]. The mechanism of TRAIL resistance is not fully understood, but accumulating evidence suggests that it is mediated by a number of proteins and their related signaling pathways, including overexpression of survival molecules and reduced expression of proapoptotic molecules. We previously identified the serine-threonine protein phosphatase 2A (PP2A) as a player that contributes to TRAIL resistance in TNBC [29].

PP2A is a member of the serine-threonine phosphatase family that regulates a number of signaling pathways [30]. PP2A holoenzymes can exert pro-apoptotic or anti-survival functions [31,32], but how PP2A regulates apoptotic signaling is not fully understood. Efforts had led to the development of the PP2A inhibitor LB-100 showing that LB-100 sensitizes cancer cells to both chemotherapy and radiotherapy [33]. Our recent study showed that the inhibition of PP2A activity by LB-100 sensitizes mesenchymal-like TNBC cells to TRAIL-induced apoptosis [34]. However, it is not clear if LB-100 can effectively inhibit the growth of TRAIL-resistant TNBC cells and if pharmacological inhibition of PP2A activity enhances the anticancer activity of conventional anticancer agents in TNBC cells. This study is aimed at evaluating the effects of LB-100 alone or in combination with clinically used chemotherapeutical agents on TNBC cell death.

Materials and methods

Cell culture

MDA-MB-231 (MDA231), MDA468, and SUM159 cells were obtained from American Type Culture Collection (ATCC) (Rockville, MD, USA). HCC1937, HCC70, BT549, and BT20 cells were provided by Dr. Guojun Wu (Wayne State University). MDA231 and MDA468 cells were grown in Dulbecco’s modified Eagle’s medium (DMEM). SUM159 cells were grown in DMEM/F12 containing 5 µg/ml insulin and 1 µg/ml hydrocortisone. HCC1937, HCC70, and BT549 cells were maintained in RPMI-1640. BT20 cells were maintained in Minimal Essential Medium (MEM). All cells were supplemented with 10% FBS and 1% penicillin and streptomycin and maintained at 37°C in a humidified atmosphere of 5% CO2.

Reagents

The reagents used in the study were as follows: FBS (Sigma-Aldrich; catalog no. F0926), penicillin-streptomycin (GE Healthcare; catalog no. SV30010), trypsin-EDTA (Gibco; catalog no. 25300–054), DMEM (Gibco; catalog no. 11995–065), DMEM/F12 (Gibco; catalog no. 21041–025), RPMI-1640 (Gibco; catalog no. 11875–093), MEM (Gibco; catalog no. 11095–080), Insulin (Gibco; catalog no. 12585–014), TRAIL (Peprotech; catalog no. 310–04), cisplatin (Sigma-Aldrich; catalog no. 232120), paclitaxel (paclitaxel injection, USP; 30mg/5ml, Mylan Inc.), LB-100 (provided by Lixte Biotechnology Holdings), thiazolyl blue tetrazolium bromide (MTT) (Sigma-Aldrich; catalog no. M2128), protein assay dye (Bio-Rad; catalog no. 500–0006), bovine serum albumin (Fisher Scientific; catalog no. BP1605-100), RIPA Buffer (Cell Signaling Technology; catalog no. 9806), PVDF membrane (Millipore-Sigma; catalog no. IPVH00010), PARP (Cell Signaling Technology; catalog no. 9542), Goat anti-Mouse IgG Alexa Fluor 680 (ThermoFisher Scientific; catalog no. A21058), Goat anti-Rabbit IgG Alexa Fluor 680 (ThermoFisher Scientific; catalog no. A21109) and actin (Sigma-Aldrich; catalog no. A1978).

MTT assays

To measure cell growth, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays were performed as described previously with slight modifications [35]. Briefly, cells were plated in 96-well plates and incubated with or without drugs in 100 µl media for 48 or 72 h. A total of 20 µl MTT solution (5 mg/ml) was added into each well and incubated at 37°C for 2 h. MTT containing medium was then removed and formazan crystals were solubilized in 100 µl of DMSO for 10 min. The optical density was measured at 570 nm using the SynergyTM-2 microplate reader (BioTek Instuments Inc., Winooski, VT, USA). IC50 was obtained using the GraphPad Prism software.

Acquired TRAIL-resistant cell lines

TRAIL-resistant MDA231 (MDA231-R) and SUM159 (SUM159-R) cell lines were established by selecting parental MDA231 and SUM159 cells with TRAIL starting with low dose and then gradually increasing up to maximum dosage of 120 ng/ml over a period of 6 months. These two pairs of TRAIL-resistant cell lines were described previously [29,36]

Western blot analysis

Western blot analysis was performed as previously described with slight modification [35]. In brief, cells were harvested with RIPA lysis buffer containing protease and phosphatase inhibitors. Cell lysate was incubated on ice for 30 min. The protein was collected following centrifugation at 12,000 rpm at 4°C for 30 min. The protein concentration was measured using Bio-Rad protein assay. A total of 40–50 μg protein lysate was loaded and subjected to 10% SDS-PAGE. The proteins were transferred to Polyvinylidene difluoride (PVDF) membrane (0.45 µM) and blocked with 3% bovine serum albumin (BSA) in Tris-buffered saline (TBS) containing 0.1% Tween-20. The membrane was incubated with specific primary antibodies overnight at 4°C, and then incubated with Alexa Fluor conjugated secondary antibodies. Signals were visualized and images were obtained on an Odyssey infrared imaging system (LI-COR) at 169 µm resolution (LI-COR Biosciences, Lincoln, NE, USA).

In vivo studies

All animal experiments were conducted in accordance with the Institutional Animal Care and Use Committee. In vivo studies were performed as described previously [37]. Briefly, 4- to 6-wk-old female athymic nu/nu mice (Charles River Laboratories) were inoculated with MDA468 cells (2 x 106) 200 μl medium in each rear flank. Treatment was initiated 2 wk following inoculation once palpable tumor was measured. LB-100 was administered twice a week by intraperitoneal injection (i.p.) at 1.5 mg/kg while paclitaxel was administered at 40 mg/kg twice, i.p. for 3 wk. Tumor volume was assessed with digital calipers and calculated as a spheroid. Tumor volume of MB468 xenografts and body weight of mice were measured during the course of the treatments. Ten mice (10) for each group were used.

Statistical analysis

All data were analyzed with Graphpad prism or MS office Excel. Data were presented as mean ± standard deviation (SD). Comparisons between groups were made using Student’s t-test.

Results

LB-100 effectively inhibits the growth of TNBC cells independent of the status of TRAIL sensitivity

Our previous study suggested that PP2A plays a role in TRAIL resistance [29], but it is not known if PP2A-mediated TRAIL resistance is a general event in TNBC cells. To this end, we treated a panel of TNBC cell lines with TRAIL or LB-100, and growth inhibition was determined by MTT assay. Figure 1(a) shows that LB-100 effectively inhibited the growth of all cell lines tested with IC50 ranging from 1.17 to 7.145 μM. Although some of the cell lines were intrinsically resistant to TRAIL, they were sensitive to LB-100. For example, HCC70 cells were a TRAIL-resistant line with an IC50 of 580 ng/ml, but they were sensitive to LB-100 with an IC50 of 1.17 μM.

Figure 1.

Figure 1.

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LB-100 inhibits cell growth in a panel of TNBC cells. HCC1937, HCC70, BT20 and MDA468 cells were treated with LB-100 (a) or TRAIL (b) for 72 h. Growth inhibition was measured using MTT assay. The MTT solutions (0.8 mg/ml) were added to the media, and cells were incubated at 37°C for 2 h. After aspirating the media, formazan crystals were dissolved in DMSO followed by spectrophotometric determination of optical density at 570 nm. IC50 values were determined by using GraphPad Prism software. All experiments were performed in triplicates.

To confirm if such inhibitory effect applies to TNBC cells that have acquired TRAIL resistance, we tested the effects of LB-100 on growth inhibition using two TRAIL-resistant TNBC cell models. We previously established TRAIL-resistant SUM159 (SUM159-R) and MDA213 (MDA231-R) cells by exposing TRAIL-sensitive SUM159 and MDA231 (SUM159-P and MDA231-P, respectively) to gradually increased concentrations of TRAIL starting from 5 ng to 120 ng/ml for over a 6-month duration [29,36]. We treated SUM159-P/SUM159-R and MDA231-P/MDA231-R cells with various doses of LB-100 for 72 h, and MTT was performed and IC50 value was calculated. While the IC50 for TRAIL in SUM159-P and SUM159-R cells were 10.7 ng/ml and >1000 ng/ml, respectively, both cell lines were equally sensitive to LB-100, reflected by IC50 value of LB-100 being 3.83 μM and 3.81 μM, respectively (Figure 2). Similar results were obtained with MDA231-P/MDA231-R cells. These data suggest that LB-100 effectively inhibits the growth of TNBC cells regardless of the status of TRAIL sensitivity.

Figure 2.

Figure 2.

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LB-100 inhibits the growth of acquired TRAIL-resistant TNBC cells. (a) Confirmation of TRAIL sensitivity in two pairs of TRAIL-resistant cell lines, SUM159-P/SUM159-R, and MDA231-P/MDA231-R by MTT assay. Cells were treated with TRAIL for 72 h. B) Determination of LB-100 sensitivity by MTT in both SUM159-P/SUM159-R and MDA231-P/MDA231-R cells. IC50 values were determined by dose–response curve using GraphPad Prism software. All experiments were done in triplicates.

LB-100 effectively inhibits the growth of TNBC in mice without apparent toxicity

To demonstrate the in vivo activity of LB-100 against the growth of TNBC xenograft models, we established MB468 xenografts in immune-deficient mice. LB-100 was administrated twice a week by intraperitoneal injection at 1.5 mg/kg while paclitaxel was administrated at 40 mg/kg bi-weekly. As shown in Figure 3, LB-100 had significant single-agent antitumor activity that led to observable tumor regressions following treatment initiation. A similar effect was observed with paclitaxel, a clinically used anti-cancer agent (Figure 3), which served as a positive control. Importantly, LB-100 treatment did not significantly decrease the body weight of mice (Figure 3(b)). These results suggest that, as tested, LB-100 was effective and well tolerated as a single agent against a TRAIL-resistant MDA468 TNBC mouse model.

Figure 3.

Figure 3.

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Effects of LB-100 or paclitaxel on tumor growth and mouse body weight in vivo. MDA468 cells (2 × 106) cells were suspended in 200 μl of the media and injected into each rear flank of immune-deficient mice. Treatment was initiated 2 wk following inoculation once palpable tumor was measured. LB-100 was administered twice a week by intraperitoneal injection (i.p.) at 1.5 mg/kg while paclitaxel was administered at 40 mg/kg twice i.p. Tumor volume was assessed with digital calipers and calculated as a spheroid. (a) Tumor volume of MDA468 xenografts in immune-deficient mice (n = 10). (b) Body weight of mice during the course of the treatments.

TRAIL or LB-100 enhances anticancer activity of clinically used chemotherapeutic agents

Since mainstay chemotherapies for patients with TNBC are anthracycline- or taxane-based treatments [38], we first asked if TRAIL can enhance anticancer activities of these conventional chemotherapies. To this end, we tested the effects of TRAIL on paclitaxel’s anticancer activity. We treated BT549 and SUM159 cells with various doses of TRAIL, paclitaxel or their combination for 48 h. As shown in Figure 4, treatments with either TRAIL or paclitaxel inhibited cell proliferation to various degrees. By contrast, combination treatments resulted in a significant reduction in cell proliferation in both cell lines. These data suggest that TRAIL enhances paclitaxel’s anticancer activity in TNBC cells. Next, we tested the effects of LB-100 on paclitaxel’s anticancer activity in these TNBC cells. We treated HCC1937 cells with LB-100, paclitaxel or their combination. We chose HCC1937 cells because TNBC cells are generally sensitive to TRAIL, but basal-like TNBC cells such as HCC1937 cells are resistant to TRAIL. We found that combination treatments significantly inhibited the growth of HCC1937 cells as compared to cells treated with TRAIL or LB-100 (Figure 4(c)). Similar results were obtained with another basal-like TNBC cell line, MDA468 cells (data not shown). Taken together, our data suggest that promoting TRAIL-induced apoptosis or pharmacological inhibition of PP2A enhances paclitaxel-induced cell death in TNBC cells.

Figure 4.

Figure 4.

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Effects of combination treatment consisting of either TRAIL or LB-100 with paclitaxel on cell growth in different TNBC cell lines. BT549 (a) and SUM159 (b) cells were treated with TRAIL, paclitaxel or their combination and growth inhibition was measured by MTT assay. (c) HCC1937 cells were treated with LB-100 and paclitaxel or their combination and growth inhibition was measured by MTT assay. All experiments were done in triplicates.

LB-100 enhances cisplatin-induced cell death by apoptosis

Because TNBC cells often exhibit a defect in DNA repair, and clinical observations indicated that some patients with TNBC have a favorable response to the DNA cross-linking agent platinum [39], we tested the effects of LB-100 on cisplatin-induced cell death in TNBC cells. We treated MDA468 cells with cisplatin, LB-100 or their combination and showed that combination of LB-100 with cisplatin significantly decreases the cell growth as compared to cells treated with either LB-100 or cisplatin (Figure 5(a)). Importantly, we found that the enhanced effect of combination treatment on growth inhibition is due to increased apoptotic cell death, as demonstrated by the appearance of cleaved PARP (Figure 5(b)). However, cleaved PARP was not apparent in cells treated with a single agent. Thus, our data suggest that enhanced apoptosis is the one of the mechanisms by which LB-100 enhances cisplatin’s efficacy in TNBC cells.

Figure 5.

Figure 5.

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LB-100 synergistically enhances cisplatin efficacy in MDA468 cells through induction of apoptosis. (a) Growth inhibition. MDA468 cells were left untreated (Ctrl) or treated with LB-100 (6.25 µM), cisplatin (Cp) (1.25 µM) or their combination (LB-100+ Cp), and growth inhibition was measured by MTT assay. All experiments were done in triplicates. (b) Detection of PARP cleavage. MDA468 cells were treated with LB-100, cisplatin or their combination and PARP levels were determined by western blot analysis. Actin was used as loading control. Cl-PARP, cleaved PARP.

Discussion

The current treatment options for patients with TNBC are not very effective. Therefore, the development of better treatments is urgently needed. The strategies for developing better cancer treatments can be either through improving the efficacy of currently clinically used chemotherapies or targeting cancer cell’s vulnerability. In this study, we attempted to address these two aspects. For cancer cell’s vulnerability, we found that LB-100 effectively inhibits the growth of TNBC cells regardless of the status of TRAIL sensitivity. For improving the efficacy of conventional chemotherapies, we showed that TRAIL or LB-100 enhances the efficacy of currently used chemotherapeutic agents including paclitaxel and cisplatin.

Since its identification, TRAIL has been an attractive agent for cancer therapies because of its specificity against cancer cells while sparing normal cells. While many cancer cells are intrinsically resistant to TRAIL, TNBC cells are sensitive to TRAIL [16]. Therefore, TRAIL-based treatment can be developed for the treatment of this aggressive cancer. However, the development of acquired TRAIL resistance limits its use as anti-cancer agent in a clinical setting. Our previous studies showed that PP2A is involved in TRAIL resistance [29], but the extent of such effects on the growth of TNBC cells is not known. In this study, we found that the PP2A inhibitor LB-100 is effective against a panel of TNBC cells with the different status of TRAIL sensitivity. For example, LB-100 is effective against MDA468 cells, a TRAIL-resistant TNBC cell line [7]. Importantly, we found that both TRAIL-resistant MDA231 and SUM159 cells are equally sensitive to TRAIL, as compared to their corresponding TRAIL-sensitive parental cells. These observations suggest that patients with TNBC can be initially treated with TRAIL and subsequently with LB-100 if tumors of these patients develop TRAIL resistance. We speculate that this strategy is also applicable to other tumors that are intrinsically sensitive to TRAIL.

Another strategy for the development of effective chemotherapies is to improve the efficacy of currently used chemotherapies. For patients with TNBC, the first line chemotherapies are taxane- and anthracycline-based treatments [5]. Although the majority of these patients initially respond to these agents, resistance to these treatments is inevitable. In this study, we showed that TRAIL sensitizes TNBC cells to either paclitaxel or cisplatin. In addition, we found that LB-100 can also sensitize TNBC cells to paclitaxel or cisplatin. More importantly, we found that LB-100 is as effective as paclitaxel against the growth of MDA468 tumors without affecting mouse weight. Since paclitaxel is the first-line chemotherapy for patients with TNBC, and side effect associated with paclitaxel treatment is noticeable [40]. In this study, we found that TRAIL or LB-100 sensitizes TNBC cells to paclitaxel. In addition, we also found that LB-100 also sensitizes TNBC cells to cisplatin. These data suggest that if the doses of paclitaxel or cisplatin in combination with LB-100 are reduced, and then the side effect associated with these agents can be decreased. In doing so, patients with TNBC will be more tolerated with paclitaxel or cisplatin and therefore, the efficacy of paclitaxel or cisplatin will improve.

Previous study indicated that the cell defense mechanism can be mediated by the PP2A-mediated signaling pathways that involve Akt1, and that LB-100 upregulates Akt1 leading to mitotic catastrophe and subsequent cell death [33]. Consistently, we found that LB-100 treatment increased Akt activation (data not shown). In addition, we found that at the lower doses, LB-100 enhances cisplatin-induced PARP cleavage, a hallmark of apoptosis. This observation is also consistent with the results obtained with ovarian cancer cells in which LB-100 enhances cisplatin-induced apoptosis [41]. Taken together, it is suggested that the combination of paclitaxel or cisplatin with LB-100 enhances the induction of apoptosis thus improving the efficacy of these agents in cancer cells including TNBC cells.

In summary, our data showed that LB-100 is potent against TNBC cells regardless of the status of TRAIL sensitivity. In addition, we found that LB-100 is also potent against TNBC cells regardless of subtypes as both mesenchymal-like and basal-like TNBC cells are sensitive to LB-100. This is important because only mesenchymal but not basal-like TNBC cells are sensitive to TRAIL [7]. In addition, TNBC cells were found to be sensitized by either TRAIL or LB-100 to paclitaxel or cisplatin. Since paclitaxel and cisplatin are commonly used for treating patients with TNBC, our data suggest that patients with TNBC can benefit from the combinational treatments of these agents with TRAIL or LB-100.

Funding Statement

This work was, in part, supported by National Institute of Health [Grant R01CA174949] through the NCI (GSW) and the Dean’s Diversity Fellowship of Wayne State University (JMP).

Acknowledgments

Dr. John Kovach from Lixte Biotechnology Holdings (East Setauket, NY) for providing LB-100. This work was, in part, supported by the NIH grant R01 CA174949 (GSW) and the Dean’s Diversity Fellowship of Wayne State University (JMP).

Disclosure statement

No potential conflict of interest was reported by the authors.

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