The Pleiotropic Role of Retinoic Acid/Retinoic Acid Receptors Signaling: From Vitamin A Metabolism to Gene Rearrangements in Acute Promyelocytic Leukemia

Conserva, Maria Rosa; Anelli, Luisa; Zagaria, Antonella; Specchia, Giorgina; Albano, Francesco

doi:10.3390/ijms20122921

Cited by 23 publications

(17 citation statements)

References 161 publications

(203 reference statements)

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“…PML-RARα alters the functions of both the transcription factor RARα and of the tumor suppressor PML, which is at the hub of the PML nuclear bodies (PML-NBs) [93]. PML-RARα disrupts the PML-NBs and acts as a transcriptional repressor through the block of RA-induced myeloid differentiation, thereby impeding the differentiation from the promyelocyte stage to granulocyte [108]. The PML-RARα fusion protein is not only a misfolded protein by itself, but also promotes aberrant folding of nuclear receptor corepressor 1 (NCOR1), a protein essential for the function of several tumor suppressors, including Max dimerization protein 1 (MAD1) [109].…”

Section: Upr Involvement In Aplmentioning

confidence: 99%

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Martelli

Paganelli

Chiarini

et al. 2020

Cancers

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The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.

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Section: Upr Involvement In Aplmentioning

confidence: 99%

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Martelli

Paganelli

Chiarini

et al. 2020

Cancers

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“…It is a natural inhibitor of human tumors and is commonly used in the treatment of many diseases (Fischer‐Huchzermeyer et al., 2017; Rizzoli & Biver, 2018). However, a large body of research has shown that long‐term use of retinoic acid can cause a variety of diseases, with OP being the most important one (Conserva, Anelli, Zagaria, Specchia, & Albano, 2019; Petkovich, Heersche, Aubin, Grigoriadis, & Jones, 1987). We therefore chose to treat rats with retinoic acid to create a secondary OP model.…”

Section: Discussionmentioning

confidence: 99%

Lactobacillus Fermentum ZS40 prevents secondary osteoporosis in Wistar Rat

Liu

Fan²,

et al. 2020

Food Science & Nutrition

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Using retinoic acid to inducer, we successfully established a rat model of secondary osteoporosis and verified the preventive effect of Lactobacillus fermentum ZS40 (ZS40) on secondary osteoporosis. Serum biochemical indicators showed that ZS40 can effectively slow down bone resorption caused by retinoic acid, increase blood content of calcium, phosphorus, bone alkaline phosphatase, bone gla protein, and insulin‐like growth factor 1, and decrease blood content of tartrate‐resistant acid phosphatase (TRAP) 5b. qRT‐PCR results showed that ZS40 could upregulate mRNA expressions of β‐catenin, Wnt10b, Lrp5, Lrp6, Runx2, ALP, RANKL, and OPG, and downregulate mRNA expression of DKK1, RANK, TRACP, and CTSK in the rats’ spinal cord. Results following TRAP staining showed that ZS40 could slow down retinoic acid‐induced formation of osteoclasts. Micro‐CT results showed that ZS40 could reduce Tb.Sp, increase BV/TV, Tb.N, Tb.Th, and ultimately increase bone mineral density of rats in vivo. These findings indicate that ZS40 might have a potential role in preventing retinoic acid‐induced secondary osteoporosis in vivo.

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“…P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) are induced by arsenic trioxide (As2O3), but are not the main mechanism of As2O3 -resistance in acute promyelocytic leukemia cells [78] Very little is known on the role of the microenvironment in APL. Several studies have shown that RARs regulates non-hematopoietic cells present in the bone marrow microenvironment influencing stem cell fate [79][80][81].…”

Section: Insight Into the Mechanisms Of Treatment Resistance In Aplmentioning

confidence: 99%

Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies

Noguera

Catalano

Banella

et al. 2019

Preprint

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In this review, we highlight new findings that have deepened our understanding of the mechanisms of leukemogenesis, therapy and resistance in APL. PML-RARa sets the cellular landscape of Acute promyelocytic leukemia (APL) by repressing transcription of RARa target genes and disrupting PML-NBs. RAR receptors control the homeostasis of tissue growth, modeling and regeneration, PML NBs are involved in self-renewal of normal and cancer stem cells, DNA damage response, senescence and stress response. Additional somatic mutations in APL mainly involve FLT3, WT1, NRAS, KRAS, ARID1B and ARID1A genes. Treatment outcomes in patients with newly diagnosed APL improved dramatically since the advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). ATRA activates the transcription of blocked genes and degrades PML-RARα, while ATO degrades PML-RARa by promoting apoptosis and has a pro-oxidant effect. Resistance to ATRA and ATO may derive from mutations in the RARa ligand binding domain (LBD) and in the PML-B2 domain of PML-RARa, but such mutations cannot explain the majority of resistances experienced in the clinic, globally accounting for 5-10% of cases. Several studies are ongoing to unravel clonal evolution and resistance, suggesting the therapeutic potential of new retinoid molecules and combinatorial treatments of ATRA or ATO with different drugs acting through alternative mechanisms of action, which may lead to synergistic effects on growth control or induction of apoptosis in APL cells.

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The Pleiotropic Role of Retinoic Acid/Retinoic Acid Receptors Signaling: From Vitamin A Metabolism to Gene Rearrangements in Acute Promyelocytic Leukemia

Cited by 23 publications

References 161 publications

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Lactobacillus Fermentum ZS40 prevents secondary osteoporosis in Wistar Rat

Acute Promyelocytic Leukemia: Update on the Mechanisms of Leukemogenesis, Resistance and on Innovative Treatment Strategies

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