Protein serine/threonine phosphatases in tumor microenvironment: a vital player and a promising therapeutic target

Abstract

The tumor microenvironment (TME) is involved in cancer initiation and progression. With advances in the TME field, numerous therapeutic approaches, such as antiangiogenic treatment and immune checkpoint inhibitors, have been inspired and developed. Nevertheless, the sophisticated regulatory effects on the biological balance of the TME remain unclear. Decoding the pathological features of the TME is urgently needed to understand the tumor ecosystem and develop novel antitumor treatments. Protein serine/threonine phosphatases (PSPs) are responsible for inverse protein phosphorylation processes. Aberrant expression and dysfunction of PSPs disturb cellular homeostasis, reprogram metabolic processes and reshape the immune landscape, thereby contributing to cancer progression. Some therapeutic implications, such as the use of PSPs as targets, have drawn the attention of researchers and clinicians. To date, the effects of PSP inhibitors are less satisfactory in real-world practice. With breakthroughs in sequencing technologies, scientists can decipher TME investigations via multiomics and higher resolution. These benefits provide an opportunity to explore the TME in a more comprehensive manner and inspire more findings concerning PSPs in the TME. The current review starts by introducing the canonical knowledge of PSPs, including their members, structures and posttranslational modifications for activities. We then summarize the functions of PSPs in regulating cellular homeostasis. In particular, we specified the up-to-date roles of PSPs in modulating the immune microenvironment, adopting hypoxia, reprogramming metabolic processes, and responding to extracellular matrix remodeling. Finally, we introduce preclinical PSP inhibitors with translational value and conclude with clinical trials of PSP inhibitors for cancer treatment.

Keywords: PSP superfamily; PSPs inhibitors; clinical translation; immune therapy; tumor microenvironment.

Figure 1

Structure of the PSPs. PP1 is comprised of catalytic and regulatory subunits. It can be inhibited by regulatory subunit-specific inhibitors. PP2A is comprised of catalytic, regulatory and scaffold subunits. Activators can stabilize the holoenzyme. Calcineurin is comprised of catalytic and regulatory subunits, which can be inhibited by inhibitors such as CSP and FK506. PP4 can form the dimer with PP4R1 or trimer with PP4R2/PP4R3. PP5 functions as a single subunit enzyme. It features a tetratricopeptide repeat domain and an autoinhibitory sequence. PPM1D is a single-unit enzyme with the B-loop facing the catalytic center. Four Asp residues facilitate the binding of metal iron. Asp: aspartic Acid, CSP: cyclosporin

Figure 2

PSPs in hypoxic adaption and diverse metabolism. (A) Hypoxic adaption: PP2A dephosphorylates PLK to inhibit cell cycle and promote dormancy. Dephosphorylation of PHD2 at Ser125 leaves HIF1A accumulation. The iron channel TRPM8, acts as a Ca2+ inflow channel, which facilitates the activation of calcineurin. Dephosphorylated RACK1 binds to HIF1A and stabilize HIF1A. Intact HIF1A regulates relative genes which contribute to hypoxic adaption. In normoxia, TBK1 is hydroxylated at Pro48, and can't be dephosphorylated by PPM1B. Under hypoxic conditions, dehydroxylated TBK1 can be dephosphorylated at Ser172, which leads to activation of downstream factors. (B) Diverse metabolism: TZDs can bind to PPARγ, which recruits PP5 to dephosphorylate PPARγ at Ser112. Dephosphorylated PPARγ is activated and targets various metabolism-related genes. PP1 is phosphorylated by NEK2. PP1 deactivation facilitates AKT regulation of glucose metabolism genes. PDP1/PDHA1 complex contributes to TCA cycle. Once acetylated on Lys321 by ACAT1, PDHA1 dissociates from PDP1 and binds to PDK1, which leads to Ser293 phosphorylation and the subsequent Warburg effect.

Figure 3

PSPs in ECM modulation and intercellular communication. (A) Matrix stiffness modulation. Fibroblasts and tumor cells regulate ECM-related genes and EMT-related genes through TGF-β pathway. PPM1A can dephosphorylate P38 to terminate this process. (B) Angiogenesis. Activation of calcineurin/NFAT/Ang2 pathway in endothelial cells contributes to angiogenesis, which provides pre-metastatic niches for lung metastasis. (C) Bone erosion. In tumor cells, PP1 dephosphorylates P38 and reduces OPG production. Reduced OPG levels lead to enhanced bone erosion and further bone metastasis. (D) Intercellular communication. PDGF-BB induces YAP accumulation. Platelet detachment contributes to PP1-MYPT1 complex activation, which can dephosphorylate YAP for cancerous properties.

Figure 4

PSPs in immune modulation. (A) In tumor cells, inflammatory factors, such as LPS activate NF-κB pathway and reduce PP2A expression. PP2A deficiency promotes kinase activation and acquires cancerous properties. PP2A deficiency activates the GAS-STING pathway to modulate immunity. PP4 deficiency facilitates STAT1 and P65 activation and cytokine production. (B) In lymphocytes, PP2A can inhibit TCR-induced mTORC1 activation and T cell activation. Moreover, elevation of the extracellular k⁺ concentration can suppress T cell functions, which is required for intact PP2A. ZFP91 promotes PP2A holoenzyme assembly and downstream effects. Besides, Ca2+ flows through the iron channel CRAC and activates calcineurin, which dephosphorylates NFAT and exposes the NLS. Activated NFAT regulates T cell activation. (C) In macrophages, TLR/TBK/IRF3 pathway promotes IFN-β production, whereas PP1 or PP2A can interrupt the process by IRF3 dephosphorylation. Additionally, PP2A dephosphorylates MST1/2 to stabilize YAP, which antagonizes TBK1 and its subsequent effects. LPS: Lipopolysaccharide, NLS: nuclear localization signal, ZFP91: Zinc finger protein 91

Figure 5

Functions and therapeutic implications of PSPs in TME. In TME, PSPs are required for both biological and cancerous functions. Regarding the essential roles of PSPs, both traditional and innovative therapeutic implications are explored for the treatment of tumors.