PP2A Inhibition Is a Common Event in Colorectal Cancer and Its Restoration Using FTY720 Shows Promising Therapeutic Potential

Abstract

Protein phosphatase 2A (PP2A) is a tumor suppressor that regulates many signaling pathways crucial for cell transformation. In fact, decreased activity of PP2A has been reported as a recurrent alteration in many types of cancer. Here, we show that PP2A is frequently inactivated in patients with colorectal cancer, indicating that PP2A represents a potential therapeutic target for this disease. We identified overexpression of the endogenous PP2A inhibitors SET and CIP2A, and downregulation of regulatory PP2A such as PPP2R2A and PPP2R5E, as contributing mechanisms to PP2A inhibition in colorectal cancer. Moreover, we observed that its restoration using FTY720 impairs proliferation and clonogenic potential of colorectal cancer cells, induces caspase-dependent apoptosis, and affects AKT and extracellular signal-regulated kinase-1/2 activation status. Interestingly, treatment with FTY720 showed an additive effect with 5-fluorouracil, SN-38, and oxaliplatin, drugs used in standard chemotherapy in patients with colorectal cancer. These results suggest that PP2A activity is commonly decreased in colorectal cancer cells, and that the use of PP2A activators, such as FTY720, might represent a potential novel therapeutic strategy in colorectal cancer. Mol Cancer Ther; 13(4); 938-47. Ó2014 AACR.

Deregulation of the PP2A Inhibitor SET Shows Promising Therapeutic Implications and Determines Poor Clinical Outcome in Patients with Metastatic Colorectal Cancer

“…As expected, these results were more evident after FTY720 treatment than after SET silencing (Supplementary Fig. S4C) probably because FTY720 acts via both SET and CIP2A inactivation (31,32). Moreover, we observed lower sensitivity of colorectal cancer cell lines to oxaliplatin and 5-FU after ectopic expression of SET ( Supplementary Fig.…”

“…Our previous results showed that PP2A inactivation is a common event in colorectal cancer and we identified SET deregulation as a possible contributing mechanism to inhibit PP2A in a set of 21 samples of patients with primary colorectal cancer (32). These results led us to hypothesize that SET could be playing an important oncogenic role in colorectal cancer.…”

“…Media were supplemented with penicillin G (100 U/mL) and streptomycin (0.1 mg/mL). Cells were treated with oxaliplatin (LOHP; 1 mmol/L; Sigma) and FTY720 (10 mmol/L; Calbiochem) as previously reported (32)(33)(34). For transfection experiments, colorectal cancer cells were seeded in 6-well plates and transfected with 10 mL of Lipofectamine 2000 (Life Technologies) and 2 mg of plasmidic vectors or 75 nmol/L of SET-specific siRNAs designed and synthesized by Dharmacon RNA Technologies.…”

“…Interestingly, it has been reported that the antitumor effects showed by the PP2A activator FTY720 are mediated by SET in lung cancer (31). Moreover, our group has recently described that PP2A inhibition is a common event in colorectal cancer and that its restoration using FTY70 or forskolin induces promising antitumor effects (32,33).…”

Regulation of polo-like kinase 1 by DNA damage and PP2A/B55α

“…41 The same study also reported that the subgroup of breast cancer patients with loss of B55a suffered poor treatment outcome and survival. 41 Others linked B55a to childhood teratoma, 42 prostate cancer, 43 colorectal cancer, 44 lung cancer, 45 and leukemia. 46 In this study we characterized B55a as a regulator of Plk1 and the DNA damage checkpoint, which finding may mechanistically explain how B55a functions as an important tumor suppressor.…”