Galectin 3 is a member of a family of β-galactoside binding proteins and has emerged as an important regulator of diverse functions critical in cancer biology including apoptosis, metastasis, immune ...surveillance, molecular trafficking, mRNA splicing, gene expression, and inflammation. Galectin 3's ability to support cancer cell survival by intra-cellular and extra-cellular mechanisms suggests this molecule is an important component of the tumor microenvironment that potentially could be targeted for therapy. Data is emerging that Galectin 3 is elevated in many cancers including solid tumors and the cancers of the blood. Galectin 3 also appears to be a key molecule produced by tumor microenvironment support cells including mesenchymal stromal cells (MSC) to suppress immune surveillance by killing T cells and interfering with NK cell function and by supporting metastasis. Levels of Galectin 3 increase in the MSC of aging mice and perhaps this contributes to the development of cancer in the elderly. Galectin 3 modulates surface protein expression of a diverse set of glycoproteins including CD44 by regulating endocytosis of these proteins. In addition, Galectin 3 binding to receptor kinases such as CD45 and the T cell receptor is critical in the regulation of their function. In this review I will examine the various mechanisms how Galectin 3 supports chemoresistance and metastasis in solid tumors and in leukemia and lymphoma. I will also discuss possible therapeutic strategies to target this Galectin for cancer therapy. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.
•Galectin 3 is a critical component of the tumor microenvironment.•Galectin 3 can suppress immune surveillance.•Galectin 3 regulates survival signaling by diverse mechanisms.
Cancer cells depend on a supportive niche (the tumor microenvironment) that promotes tumor cell survival while protecting the malignant cells from therapeutic challenges and the host's defense ...systems. Cancer cells and the support cells in the tumor microenvironment communicate via cytokines/chemokines, cell:cell contact, or alterations in the metabolic state of the niche (e.g. hypoxia) that promote growth and survival of the tumor cell, influence metastasis, and defeat immune surveillance. These signaling pathways involve dysregulation of not only protein kinases but also protein phosphatases as normal signal transduction processes require both activation and deactivation. For instance, aberrant receptor signaling can result from constitutive activation of a tyrosine kinase such as FLT3 or inactivation of a tyrosine protein phosphatase such as SHP-2 (PTPN11). Activation of serine/threonine kinases such as AKT and ERK are often observed during the development of drug resistance while genomic and non-genomic suppression of serine/threonine protein phosphatases such as PP2A achieve similar results. It is fairly clear that the various protein phosphatases will impact processes that support drug resistance. Of growing interest is the emerging model whereby the support cells in the tumor microenvironment actually serve as drivers of tumorigenesis. This phenomenon has been most prominently observed in osteoblast cells in leukemic niches. At least one protein phosphatase, PTPN11, has emerged as a critical driver of this process in juvenile myelomonocytic leukemia. This review will cover the role of various serine/threonine and tyrosine protein phosphatases in processes that are central to tumor microenvironment function.
•Protein Phosphatases regulate diverse cascades in the tumor microenvironment (TME).•PTPN11 mutations in stromal cells can drive leukemogenesis.•PTPN11 and PPP2R2A influence MSC differentiation to pro-tumor cell types in the TME.
Aberrant activation of signal transduction pathways can transform a normal cell to a malignant one and can impart survival properties that render cancer cells resistant to therapy. A diverse set of ...cascades have been implicated in various cancers including those mediated by serine/threonine kinases such RAS, PI3K/AKT, and PKC. Signal transduction is a dynamic process involving both “On” and “Off” switches. Activating mutations of RAS or PI3K can be viewed as the switch being stuck in the “On” position resulting in continued signaling by a survival and/or proliferation pathway. On the other hand, inactivation of protein phosphatases such as the PP2A family can be seen as the defective “Off” switch that similarly can activate these pathways. A problem for therapeutic targeting of PP2A is that the enzyme is a hetero-trimer and thus drug targeting involves complex structures. More importantly, since PP2A isoforms generally act as tumor suppressors one would want to activate these enzymes rather than suppress them. The elucidation of the role of cellular inhibitors like SET and CIP2A in cancer suggests that targeting these proteins can have therapeutic efficacy by mechanisms involving PP2A activation. Furthermore, drugs such as FTY-720 can activate PP2A isoforms directly. This review will cover the current state of knowledge of PP2A role as a tumor suppressor in cancer cells and as a mediator of processes that can impact drug resistance and immune surveillance.
•PP2A isoforms regulate diverse signaling cascades impacting cancer cell transformation and survival in the microenvironment.•Some PP2A isoforms are tumor suppressors and others tumor promoters.•PP2A is emerging as a critical regulator of immune checkpoint inhibition.
The sphingolipid ceramide has proven to be a powerful second-signal effector molecule that regulates diverse cellular processes including apoptosis, cell senescence, the cell cycle, and cellular ...differentiation. Ceramide has been shown to activate a number of enzymes involved in stress signaling cascades including both protein kinases and protein phosphatases. Ceramide kinase targets include stress-activated protein kinases (SAPKs) such as the jun kinases (JNKs), kinase suppressor of Ras (KSR), and the atypical protein kinase C (PKC) isoform, PKC ζ. Ceramide also is capable of activating protein phosphatases such as protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A). It is through these protein phosphatases that ceramide can indirectly inhibit kinases that are key components of pro-growth signaling processes such as the classical and novel PKC isoforms and protein kinase B (PKB; also known as Akt). However, the mechanisms how ceramide
directly activates enzymes such as JNK and PP2A are still not clear. Elucidation of these mechanisms will reveal how ceramide functions in stress signaling cascades and will provide important information on cellular processes such as apoptosis. It is becoming clear that the ceramide generation is a near universal feature of programmed cell death. It is possible that during at least some apoptotic events, ceramide may be required to activate stress-signal cascades that lead to cell death, while concurrently, suppressing growth and survival pathways in the dying cell. Such a versatile role for ceramide is not unreasonable since ceramide has been implicated as having a role in both intrinsic (i.e. mitochondrial) and extrinsic (i.e. death receptor-mediated) apoptotic pathways. The recent data suggesting that aberrant glycosylation of ceramide (i.e. inactivation of the molecule) may be an important cause of drug resistance in certain cancers suggests that ceramide-mediated signaling cascades are critical components of chemotherapy-induced cell killing. Taken together, these properties of ceramide suggest that this important second-signal molecule may be an important target in anti-neoplastic strategies.
LGALS1 acts as a pro-survival molecule in AML Ruvolo, Peter P.; Ma, Huaxian; Ruvolo, Vivian R. ...
Biochimica et biophysica acta. Molecular cell research,
October 2020, 2020-10-00, 20201001, Letnik:
1867, Številka:
10
Journal Article
Recenzirano
Odprti dostop
The galectin LGALS1 is a glycan binding protein that regulates intracellular (e.g. signal transduction) and extracellular processes (e.g. immunity, leukocyte mobilization) that support cell survival. ...The protein is best known for its role in RAS signaling. LGALS1 is important in acute lymphoblastic leukemia but its role in acute myeloid leukemia is not well defined. We previously found suppression of LGALS1 in AML cell lines OCI-AML3 and THP-1 sensitized both cell lines to BCL2 inhibitor ABT-737. In this study, we used an in vivo murine OCI-AML3 xenograft model to test whether reduction expression of LGALS1 affects survival. Mice bearing the OCI-AML3 cells with LGALS1 shRNA survived significantly longer than mice with control OCI-AML3 cells. Gene expression profiling using RNASeq was performed using the control and LGALS1 shRNA of p53 WT OCI-AML3 and p53 mutant THP-1 cells. The data reveal distinct differences between the two cell lines in number of genes affected, in pathways associated with these genes, in expression of oncogenes, and in the transcription factors involved. The p53 pathway is prominent in OCI-AML3 cells. An examination of LGALS1 mRNA in an AML patient population reveals elevated LGALS1 mRNA is associated with shorter disease free survival and increased blasts in the BM. This data with the xenograft model data presented suggest LGALS1 may be important in the AML microenvironment. In summary, the data presented here suggest that a strategy targeting LGALS1 may benefit AML patients.
•LGALS1 suppression in an in vivo AML model prolongs survival of mice.•LGALS1 suppression in an in vivo AML model reduces tumor burden of mice.•LGALS1 suppression alters gene expression and networks affected depend on p53 status.•AML patients with elevated LGALS1 mRNA result in reduced disease free survival.
B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. ...Here, we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC50 was approximately 10 nmol/L, and cell death occurred within 2 hours. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia, a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profiling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on-target mitochondrial mechanism of action. Our protein and BH3 profiling studies provide promising tools that can be tested as predictive biomarkers in any clinical trial of ABT-199 in AML.
The regulation of protein kinase B (AKT) is a dynamic process that depends on the balance between phosphorylation by upstream kinases for activation and inactivation by dephosphorylation by protein ...phosphatases. Phosphorylated AKT is commonly found in acute myeloid leukemia (AML) and confers an unfavorable prognosis. Understanding the relative importance of upstream kinases and AKT phosphatase in the activation of AKT is relevant for the therapeutic targeting of this signaling axis in AML. The B55α subunit of protein phosphatase 2A (PP2A) has been implicated in AKT dephosphorylation, but its role in regulating AKT in AML is unknown. We examined B55α protein expression in blast cells derived from 511 AML patients using reverse phase protein analysis. B55α protein expression was lower in AML cells compared with normal CD34+ cells. B55α protein levels negatively correlated with threonine 308 phosphorylation levels. Low levels of B55α were associated with shorter complete remission duration, demonstrating that decreased expression is an adverse prognostic factor in AML. These findings suggest that decreased B55α expression in AML is at least partially responsible for increased AKT signaling in AML and suggests that therapeutic targeting of PP2A could counteract this.
The Ras/Raf/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway is often implicated in sensitivity and resistance to leukemia therapy. Dysregulated signaling ...through the Ras/Raf/MEK/ERK pathway is often the result of genetic alterations in critical components in this pathway as well as mutations at upstream growth factor receptors. Unrestricted leukemia proliferation and decreased sensitivity to apoptotic-inducing agents and chemoresistance are typically associated with activation of pro-survival pathways. Mutations in this pathway and upstream signaling molecules can alter sensitivity to small molecule inhibitors targeting components of this cascade as well as to inhibitors targeting other key pathways (for example, phosphatidylinositol 3 kinase (PI3K)/phosphatase and tensin homologue deleted on chromosome 10 (PTEN)/Akt/mammalian target of rapamycin (mTOR)) activated in leukemia. Similarly, PI3K mutations can result in resistance to inhibitors targeting the Ras/Raf/MEK/ERK pathway, indicating important interaction points between the pathways (cross-talk). Furthermore, the Ras/Raf/MEK/ERK pathway can be activated by chemotherapeutic drugs commonly used in leukemia therapy. This review discusses the mechanisms by which abnormal expression of the Ras/Raf/MEK/ERK pathway can contribute to drug resistance as well as resistance to targeted leukemia therapy. Controlling the expression of this pathway could improve leukemia therapy and ameliorate human health.
It has become apparent that regulation of protein translation is an important determinant in controlling cell growth and leukemic transformation. The phosphoinositide 3-kinase (PI3K)/phosphatase and ...tensin homologue deleted on chromosome ten (PTEN)/Akt/mammalian target of rapamycin (mTOR) pathway is often implicated in sensitivity and resistance to therapy. Dysregulated signaling through the PI3K/PTEN/Akt/mTOR pathway is often the result of genetic alterations in critical components in this pathway as well as mutations at upstream growth factor receptors. Furthermore, this pathway is activated by autocrine transformation mechanisms. PTEN is a critical tumor suppressor gene and its dysregulation results in the activation of Akt. PTEN is often mutated, silenced and is often haploinsufficient. The mTOR complex1 (mTORC1) regulates the assembly of the eukaryotic initiation factor4F complex, which is critical for the translation of mRNAs that are important for cell growth, prevention of apoptosis and transformation. These mRNAs have long 5'-untranslated regions that are G+C rich, rendering them difficult to translate. Elevated mTORC1 activity promotes the translation of these mRNAs via the phosphorylation of 4E-BP1. mTORC1 is a target of rapamycin and novel active-site inhibitors that directly target the TOR kinase activity. Although rapamycin and novel rapalogs are usually cytostatic and not cytotoxic for leukemic cells, novel inhibitors that target the kinase activities of PI3K and mTOR may prove more effective for leukemia therapy.
Members of the Bcl2 family of proteins are important regulators of programmed cell death pathways with individual members that can suppress (eg Bcl2, Bcl-XL) or promote (eg Bax, Bad) apoptosis. While ...the mechanism(s) of Bcl2's anti-apoptotic function is not yet clear, introduction of Bcl2 into most eukaryotic cell types will protect the recipient cell from a wide variety of stress applications that lead to cell death. There are, however, physiologic situations in which Bcl2 expression apparently fails to protect cells from apoptosis (eg negative selection of thymocytes). Further, Bcl2 expression in patient tumor samples does not consistently correlate with a worse outcome or resistance to anticancer therapies. For example, patient response and survival following chemotherapy is independent of Bcl2 expression at least for pediatric patients with ALL. These findings indicate that simple expression of Bcl2 may not be enough to functionally protect cells from apoptosis. The finding that Bcl2 is post-translationally modified by phosphorylation suggests another level of regulation of function. Recent studies have shown that agonist-activated phosphorylation of Bcl2 at serine 70 (single site phosphorylation), a site within the flexible loop domain (FLD), is required for Bcl2's full and potent anti-apoptotic function, at least in murine IL-3-dependent myeloid cell lines. Several protein kinases have now been demonstrated to be physiologic Bcl2 kinases indicating the importance of this post-translational modification. Since Bcl2 phosphorylation has been found to be a dynamic process involving both a Bcl2 kinase(s) and phosphatase(s), a mechanism exists to rapidly and reversibly regulate Bcl2's activity and affect cell viability. In addition, multisite Bcl2 phosphorylation induced by anti-mitotic drugs like paclitaxel may inhibit Bcl2 indicating the potential wide range of functional consequences that this post-translational modification may have on function. While post-translational mechanisms other than phosphorylation may also regulate Bcl2's function (eg ubiquitination), this review will focus on the regulatory role for phosphorylation and discuss its potential clinical ramifications.
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