Perphenazine exerts antitumor effects on HUT78 cells through Akt dephosphorylation by protein phosphatase 2A

Abstract

Sezary syndrome is a rare type of non-Hodgkin lymphoma. Protein phosphatase 2A (PP2A) is an important tumor suppressor whose activity is widely inhibited in a variety of tumors. Recently, reactivation of PP2A has attracted increasing attention as a promising approach for cancer therapy. Phenothiazine anti-psychotic perphenazine (PPZ) exerts antitumor effects by reactivating PP2A. The present study investigated the molecular mechanism underling the antitumor effects of PPZ in the neuroblastoma rat sarcoma oncogene ( NRAS) -mutated Sezary syndrome cell line, HUT78. The results of the present study demonstrated that PPZ induced the dephosphorylation of Akt and ERK1/2, and triggered apoptosis in HUT78 cells. In addition, a PP2A inhibitor blocked the PPZ-mediated dephosphorylation of Akt but did not affect that of ERK1/2. The pharmacological inhibition of Akt and ERK1/2 signaling revealed that Akt activity serves an important role in the survival of HUT78 cells. The present data suggested that suppressing Akt activity by PP2A activation may be an attractive antitumor strategy for NRAS -mutated Sezary syndrome.

Drug‐like sphingolipid SH‐BC‐893 opposes ceramide‐induced mitochondrial fission and corrects diet‐induced obesity

“…Although several structurally distinct PP2A agonists have been described (Ruvolo, 2016 ), other PP2A agonists may not recapitulate the anti‐obesogenic effects of SH‐BC‐893 due to distinct modes of PP2A activation and/or their significant off‐target actions (Lee & Choi, 2016 ). Many PP2A agonists inactivate AKT (Gutierrez et al , 2014 ; Suman et al , 2016 ; Tohmé et al , 2019 ; Tsuji et al , 2021 ) which makes them ill‐suited for use as obesity therapies as they would cause insulin resistance. SH‐BC‐893 does not reduce AKT phosphorylation (Kubiniok et al , 2019 ), most likely because it activates PP2A through a different mechanism than other agonists.…”

Protein phosphatase 6 regulates trametinib sensitivity, a mitogen-activated protein kinase kinase (MEK) inhibitor, by regulating MEK1/2-ERK1/2 signaling in canine melanoma cells

“… ). MEK1/2 has been reported to activate ERK1/2 [ 25 ]. Therefore, we analyzed the effect of PP6 knockdown on the activation of ERK1/2 by evaluating the phosphorylation levels.…”

Design, Synthesis, and Validation of a Novel [11C]Promethazine PET Probe for Imaging Abeta Using Autoradiography

“…Phenothiazine analogs have versatile applications across many diseases, including antimicrobial effects [ 24 , 25 , 26 ], antitumor effects [ 27 , 28 , 29 , 30 , 31 , 32 , 33 ], and potential roles in the treatment of neurodegenerative disease [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. In the past, we showed PMZ binds to Abeta available in the brain lysate of 5XFAD mice in an in vitro study.…”