bims-apauto 2021-07-04 papers

bims-apauto

Biomed News

on Apoptosis and autophagy

Issue of 2021–07–04
nine papers selected by
Su Hyun Lee, Seoul National University

Autophagy a Close Relative of AML Biology.
Repurposing Niclosamide for Targeting Pancreatic Cancer by Inhibiting Hh/Gli Non-Canonical Axis of Gsk3β.
Asparagine: A Metabolite to Be Targeted in Cancers.
iCAL: a new pipeline to investigate autophagy selectivity and cancer.
A Structural Approach into Drug Discovery Based on Autophagy.
V600EBRAF Inhibition Induces Cytoprotective Autophagy through AMPK in Thyroid Cancer Cells.
Targeting Growth Factor Signaling Pathways in Pancreatic Cancer: Towards Inhibiting Chemoresistance.
Ubiquitin-Conjugating Enzymes in Cancer.
A Key Pathway to Cancer Resilience: The Role of Autophagy in Glioblastomas.

Biology (Basel). 2021 Jun 18. pii: 552. [Epub ahead of print]10(6):

Autophagy a Close Relative of AML Biology.

Carine Joffre, Charlotte Ducau, Laura Poillet-Perez, Charly Courdy, Véronique Mansat-De Mas.

  Autophagy, which literally means "eat yourself", is more than just a lysosomal degradation pathway. It is a well-known regulator of cellular metabolism and a mechanism implicated in tumor initiation/progression and therapeutic resistance in many cancers. However, whether autophagy acts as a tumor suppressor or promoter is still a matter of debate. In acute myeloid leukemia (AML), it is now proven that autophagy supports cell proliferation in vitro and leukemic progression in vivo. Mitophagy, the specific degradation of mitochondria through autophagy, was recently shown to be required for leukemic stem cell functions and survival, highlighting the prominent role of this selective autophagy in leukemia initiation and progression. Moreover, autophagy in AML sustains fatty acid oxidation through lipophagy to support mitochondrial oxidative phosphorylation (OxPHOS), a hallmark of chemotherapy-resistant cells. Nevertheless, in the context of therapy, in AML, as well as in other cancers, autophagy could be either cytoprotective or cytotoxic, depending on the drugs used. This review summarizes the recent findings that mechanistically show how autophagy favors leukemic transformation of normal hematopoietic stem cells, as well as AML progression and also recapitulates its ambivalent role in resistance to chemotherapies and targeted therapies.

Keywords:  AML; autophagy; hematopoiesis; mitophagy; therapy

DOI:  https://doi.org/10.3390/biology10060552
Cancers (Basel). 2021 Jun 22. pii: 3105. [Epub ahead of print]13(13):

Repurposing Niclosamide for Targeting Pancreatic Cancer by Inhibiting Hh/Gli Non-Canonical Axis of Gsk3β.

Jyoti B Kaushal, Rakesh Bhatia, Ranjana K Kanchan, Pratima Raut, Surya Mallapragada, Quan P Ly, Surinder K Batra, Satyanarayana Rachagani.

  Niclosamide (Nic), an FDA-approved anthelmintic drug, is reported to have anti-cancer efficacy and is being assessed in clinical trials for various solid tumors. Based on its ability to target multiple signaling pathways, in the present study, we evaluated the therapeutic efficacy of Nic on pancreatic cancer (PC) in vitro. We observed an anti-cancerous effect of this drug as shown by the G0/G1 phase cell cycle arrest, inhibition of PC cell viability, colony formation, and migration. Our results revealed the involvement of mitochondrial stress and mTORC1-dependent autophagy as the predominant players of Nic-induced PC cell death. Significant reduction of Nic-induced reactive oxygen species (ROS) and cell death in the presence of a selective autophagy inhibitor spautin-1 demonstrated autophagy as a major contributor to Nic-mediated cell death. Mechanistically, Nic inhibited the interaction between BCL2 and Beclin-1 that supported the crosstalk of autophagy and apoptosis. Further, Nic treatment resulted in Gsk3β inactivation by phosphorylating its Ser-9 residue leading to upregulation of Sufu and Gli3, thereby negatively impacting hedgehog signaling and cell survival. Nic induced autophagic cell death, and p-Gsk3b mediated Sufu/Gli3 cascade was further confirmed by Gsk3β activator, LY-294002, by rescuing inactivation of Hh signaling upon Nic treatment. These results suggested the involvement of a non-canonical mechanism of Hh signaling, where p-Gsk3β acts as a negative regulator of Hh/Gli1 cascade and a positive regulator of autophagy-mediated cell death. Overall, this study established the therapeutic efficacy of Nic for PC by targeting p-Gsk3β mediated non-canonical Hh signaling and promoting mTORC1-dependent autophagy and cell death.

Keywords:  Gsk3β; Hh signaling; apoptosis; autophagy; niclosamide; pancreatic cancer

DOI:  https://doi.org/10.3390/cancers13133105
Metabolites. 2021 Jun 19. pii: 402. [Epub ahead of print]11(6):

Asparagine: A Metabolite to Be Targeted in Cancers.

Jie Jiang, Sandeep Batra, Ji Zhang.

  Amino acids play central roles in cancer progression beyond their function as building blocks for protein synthesis. Thus, targeting amino acid acquisition and utilization has been proved to be therapeutically beneficial in various pre-clinical models. In this regard, depletion of circulating asparagine, a nonessential amino acid, by L-asparaginase has been used in treating pediatric acute lymphoblastic leukemia (ALL) for decades. Of interest, unlike most solid tumor cells, ALL cells lack the ability to synthesize their own asparagine de novo effectively. However, only until recently, growing evidence suggests that solid tumor cells strive to acquire adequate amounts of asparagine to support tumor progression. This process is subjected to the regulation at various levels, including oncogenic signal, tumor-niche interaction, intratumor heterogeneity and dietary accessibility. We will review the literature on L-asparaginase-based therapy as well as recent understanding of asparagine metabolism in solid tumor progression, with the hope of shedding light into a broader cancer therapeutic strategy by perturbing its acquisition and utilization.

Keywords:  ATF4; GCN2; L-asparaginase; acute lymphoblastic leukemia; asparagine; asparagine synthetase; mTORC1; metabolic adaptation; stress response

DOI:  https://doi.org/10.3390/metabo11060402
Autophagy. 2021 Jun 28. 1-3

iCAL: a new pipeline to investigate autophagy selectivity and cancer.

Weizhi Zhang, Zhu Han, Yu Xue, Da Jia.

  Macroautophagy/autophagy can selectively degrade misfolded proteins, damaged organelles and other cargoes. It is conceivable that alteration of the degradation processes could disrupt normal cellular signaling and contribute to human diseases such as cancer. To explore the link between aberrant autophagy selectivity and human cancer, we have developed a pipeline called "inference of cancer-associated LC3-interacting region-containing proteins" (iCAL), which integrates a sequence-based predictor, a model-based computational method, publicly available cancer mutations, and multiple experimental approaches. Using iCAL, we have identified 222 LIR motif-associated mutations (LAMs) in 148 LIR-containing proteins (LIRCPs), and validated that LAMs in ATG4B, STBD1, EHMT2 and BRAF impair their interactions with LC3 and/or autophagy activities. Moreover, we uncovered that STBD1, a previously poorly-characterized protein, inhibits tumor growth via metabolism reprogramming in cancer cells. A patient-derived mutation in STBD1 (W203C) disrupts the interaction with LC3 and promotes tumor growth. Taken together, iCAL provides an exciting new avenue to discover novel autophagy pathways that contribute to carcinogenesis.

Keywords:  Autophagy; LIR; STBD1; cancer; cancer mutation; glycophagy; selective autophagy

DOI:  https://doi.org/10.1080/15548627.2021.1939972
Life (Basel). 2021 Jun 04. pii: 526. [Epub ahead of print]11(6):

A Structural Approach into Drug Discovery Based on Autophagy.

Sung-Min Kang, Do-Hee Kim.

  Autophagy is a lysosome-dependent intracellular degradation machinery that plays an essential role in the regulation of cellular homeostasis. As many studies have revealed that autophagy is related to cancer, neurodegenerative diseases, metabolic diseases, and so on, and it is considered as a promising drug target. Recent advances in structural determination and computational technologies provide important structural information on essential autophagy-related proteins. Combined with high-throughput screening methods, structure-activity relationship studies have led to the discovery of molecules that modulate autophagy. In this review, we summarize the recent structural studies on autophagy-related proteins and the discovery of modulators, indicating that targeting autophagy can be utilized as an effective strategy for novel drug development.

Keywords:  autophagy; drug discovery; protein structure

DOI:  https://doi.org/10.3390/life11060526
Int J Mol Sci. 2021 Jun 03. pii: 6033. [Epub ahead of print]22(11):

V600EBRAF Inhibition Induces Cytoprotective Autophagy through AMPK in Thyroid Cancer Cells.

Eva Jiménez-Mora, Beatriz Gallego, Sergio Díaz-Gago, Marina Lasa, Pablo Baquero, Antonio Chiloeches.

  The dysregulation of autophagy is important in the development of many cancers, including thyroid cancer, where V600EBRAF is a main oncogene. Here, we analyse the effect of V600EBRAF inhibition on autophagy, the mechanisms involved in this regulation and the role of autophagy in cell survival of thyroid cancer cells. We reveal that the inhibition of V600EBRAF activity with its specific inhibitor PLX4720 or the depletion of its expression by siRNA induces autophagy in thyroid tumour cells. We show that V600EBRAF downregulation increases LKB1-AMPK signalling and decreases mTOR activity through a MEK/ERK-dependent mechanism. Moreover, we demonstrate that PLX4720 activates ULK1 and increases autophagy through the activation of the AMPK-ULK1 pathway, but not by the inhibition of mTOR. In addition, we find that autophagy blockade decreases cell viability and sensitize thyroid cancer cells to V600EBRAF inhibition by PLX4720 treatment. Finally, we generate a thyroid xenograft model to demonstrate that autophagy inhibition synergistically enhances the anti-proliferative and pro-apoptotic effects of V600EBRAF inhibition in vivo. Collectively, we uncover a new role of AMPK in mediating the induction of cytoprotective autophagy by V600EBRAF inhibition. In addition, these data establish a rationale for designing an integrated therapy targeting V600EBRAF and the LKB1-AMPK-ULK1-autophagy axis for the treatment of V600EBRAF-positive thyroid tumours.

Keywords:  AMPK; LKB1; ULK1; V600EBRAF; autophagy; survival; thyroid cancer

DOI:  https://doi.org/10.3390/ijms22116033
Front Oncol. 2021 ;11 683788

Targeting Growth Factor Signaling Pathways in Pancreatic Cancer: Towards Inhibiting Chemoresistance.

Ntombikayise Xelwa, Geoffrey Patrick Candy, John Devar, Jones Omoshoro-Jones, Martin Smith, Ekene Emmanuel Nweke.

  Pancreatic cancer is one of the most deadly cancers, ranking amongst the top leading cause of cancer related deaths in developed countries. Features such as dense stroma microenvironment, abnormal signaling pathways, and genetic heterogeneity of the tumors contribute to its chemoresistant characteristics. Amongst these features, growth factors have been observed to play crucial roles in cancer cell survival, progression, and chemoresistance. Here we review the role of the individual growth factors in pancreatic cancer chemoresistance. Importantly, the interplay between the tumor microenvironment and chemoresistance is explored in the context of pivotal role played by growth factors. We further describe current and future potential therapeutic targeting of these factors.

Keywords:  chemoresistance; chemotherapy; growth factors; pancreatic cancer; signaling pathways

DOI:  https://doi.org/10.3389/fonc.2021.683788
Cells. 2021 Jun 04. pii: 1383. [Epub ahead of print]10(6):

Ubiquitin-Conjugating Enzymes in Cancer.

Quyen Thu Bui, Jeong Hee Hong, Minseok Kwak, Ji Yeon Lee, Peter Chang-Whan Lee.

  The ubiquitin-mediated degradation system is responsible for controlling various tumor-promoting processes, including DNA repair, cell cycle arrest, cell proliferation, apoptosis, angiogenesis, migration and invasion, metastasis, and drug resistance. The conjugation of ubiquitin to a target protein is mediated sequentially by the E1 (activating)‒E2 (conjugating)‒E3 (ligating) enzyme cascade. Thus, E2 enzymes act as the central players in the ubiquitination system, modulating various pathophysiological processes in the tumor microenvironment. In this review, we summarize the types and functions of E2s in various types of cancer and discuss the possibility of E2s as targets of anticancer therapeutic strategies.

Keywords:  cancer; ubiquitin-conjugating enzyme; ubiquitination

DOI:  https://doi.org/10.3390/cells10061383
Front Oncol. 2021 ;11 652133

A Key Pathway to Cancer Resilience: The Role of Autophagy in Glioblastomas.

Elisa Helena Farias Jandrey, Marcelle Bezerra, Lilian Tiemi Inoue, Frank B Furnari, Anamaria Aranha Camargo, Érico Tosoni Costa.

  There are no effective strategies for the successful treatment of glioblastomas (GBM). Current therapeutic modalities effectively target bulk tumor cells but leave behind marginal GBM cells that escape from the surgical margins and radiotherapy field, exhibiting high migratory phenotype and resistance to all available anti-glioma therapies. Drug resistance is mostly driven by tumor cell plasticity: a concept associated with reactivating transcriptional programs in response to adverse and dynamic conditions from the tumor microenvironment. Autophagy, or "self-eating", pathway is an emerging target for cancer therapy and has been regarded as one of the key drivers of cell plasticity in response to energy demanding stress conditions. Many studies shed light on the importance of autophagy as an adaptive mechanism, protecting GBM cells from unfavorable conditions, while others recognize that autophagy can kill those cells by triggering a non-apoptotic cell death program, called 'autophagy cell death' (ACD). In this review, we carefully analyzed literature data and conclude that there is no clear evidence indicating the presence of ACD under pathophysiological settings in GBM disease. It seems to be exclusively induced by excessive (supra-physiological) stress signals, mostly from in vitro cell culture studies. Instead, pre-clinical and clinical data indicate that autophagy is an emblematic example of the 'dark-side' of a rescue pathway that contributes profoundly to a pro-tumoral adaptive response. From a standpoint of treating the real human disease, only combinatorial therapy targeting autophagy with cytotoxic drugs in the adjuvant setting for GBM patients, associated with the development of less toxic and more specific autophagy inhibitors, may inhibit adaptive response and enhance the sensibility of glioma cells to conventional therapies.

Keywords:  autophagy; cell invasion; drug resistance; glioblastoma; intratumoral heterogeneity (ITH); pro-tumoral

DOI:  https://doi.org/10.3389/fonc.2021.652133