bims-pimaco 2021-10-24 papers

on PI3K and MAPK signalling in colorectal cancer

Issue of 2021–10–24
seven papers selected by
Lucas B. Zeiger, CRUK Scotland Institute, Beatson Institute for Cancer Research

RICTOR Affects Melanoma Tumorigenesis and Its Resistance to Targeted Therapy.
DIRAS3: An Imprinted tumor suppressor gene that regulates RAS and PI3K-driven cancer growth, motility, autophagy and tumor dormancy.
Generating a New Mouse Model for Nuclear PTEN Deficiency by a Single K13R Mutation.
Lipid Profiles of RAS Nanoclusters Regulate RAS Function.
YB-1 Oncoprotein Controls PI3K/Akt Pathway by Reducing Pten Protein Level.
The Role of Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3 in the Pathogenesis of Human Cancer.
SGK1, autophagy and cancer: an overview.

Biomedicines. 2021 Oct 19. pii: 1498. [Epub ahead of print]9(10):

RICTOR Affects Melanoma Tumorigenesis and Its Resistance to Targeted Therapy.

Ahlem Jebali, Maxime Battistella, Céleste Lebbé, Nicolas Dumaz.

  The network defined by phosphatidylinositol-3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR) plays a major role in melanoma oncogenesis and has been implicated in BRAF inhibitor resistance. The central role of RICTOR (rapamycin-insensitive companion of mTOR) in this pathway has only recently begun to be unraveled. In the present study, we assessed the role of mTORC2/RICTOR in BRAF-mutated melanomas and their resistance to BRAF inhibition. We showed that RICTOR was significantly overexpressed in melanoma and associated with bad prognoses. RICTOR overexpression stimulated melanoma-initiating cells (MICs) with 'stemness' properties. We also showed that RICTOR contributed to melanoma resistance to BRAF inhibitors and rendered the cells very sensitive to mTORC2 inhibition. We highlighted a connection between mTORC2/RICTOR and STAT3 in resistant cells and revealed an interaction between RAS and RICTOR in resistant melanoma, which, when disrupted, impeded the proliferation of resistant cells. Therefore, as a key signaling node, RICTOR contributes to BRAF-dependent melanoma development and resistance to therapy and, as such, is a valuable therapeutic target in melanoma.

Keywords:  BRAF; BRAF inhibitors; mTOR; mTOR inhibitors; mTORC2; melanoma; resistance

DOI:  https://doi.org/10.3390/biomedicines9101498
Mol Cancer Ther. 2021 Oct 19. pii: molcanther.0331.2021. [Epub ahead of print]

DIRAS3: An Imprinted tumor suppressor gene that regulates RAS and PI3K-driven cancer growth, motility, autophagy and tumor dormancy.

Gamze Bildik, Xiaowen Liang, Margie N Sutton, Robert C Bast, Zhen Lu.

DIRAS3 is an imprinted tumor suppressor gene that encodes a 26 kD GTPase with 60% amino acid homology to RAS, but with a distinctive 34 amino acid N-terminal extension required to block RAS function. DIRAS3 is maternally imprinted and expressed only from the paternal allele in normal cells. Loss of expression can occur in a single "hit" through multiple mechanisms. Downregulation of DIRAS3 occurs in cancers of the ovary, breast, lung, prostate, colon, brain, and thyroid. Re-expression of DIRAS3 inhibits signaling through PI3 kinase/AKT, JAK/STAT and RAS/MAPK, blocking malignant transformation, inhibiting cancer cell growth and motility and preventing angiogenesis. DIRAS3 is a unique endogenous RAS inhibitor that binds directly to RAS, disrupting RAS dimers and clusters and preventing RAS-induced transformation. DIRAS3 is essential for autophagy and triggers this process through multiple mechanisms. Re-expression of DIRAS3 induces dormancy in a nu/nu mouse xenograft model of ovarian cancer, inhibiting cancer cell growth and angiogenesis. DIRAS3-mediated induction of autophagy facilitates the survival of dormant cancer cells in a nutrient-poor environment. DIRAS3 expression in dormant, drug-resistant autophagic cancer cells can serve as a biomarker and as a target for novel therapy to eliminate the residual disease that remains after conventional therapy.

DOI: https://doi.org/10.1158/1535-7163.MCT-21-0331
Genes Cells. 2021 Oct 18.

Generating a New Mouse Model for Nuclear PTEN Deficiency by a Single K13R Mutation.

Takashi Kato, Atsushi Igarashi, Hiromi Sesaki, Miho Iijima.

  Many human diseases, including cancer and neurological abnormalities, are linked to deficiencies of PTEN, a dual phosphatase that dephosphorylates both lipids and proteins. PTEN functions in multiple intracellular locations, including the plasma membrane and nucleus. Therefore, a critical challenge to understand the pathogenesis of PTEN-associated diseases is to determine the specific role of PTEN at different locations. Toward this goal, the current study generated a mouse line in which lysine 13, which is critical for the nuclear localization of PTEN, is changed to arginine in the lipid-binding domain using the CRISPR-Ca9 gene-editing system. We found that PTENK13R mice show a strong decrease in the localization of PTEN in the nucleus without affecting the protein stability, phosphatase activity, and phosphorylation in the C-terminal tail region. PTENK13R mice are viable but produce smaller neurons and develop microcephaly. These data demonstrate that PTENK13R mice provide a useful animal model to study the role of PTEN in the nucleus in vivo.

Keywords:  Brain; Mouse; Neuron; Nuclear PTEN; PTEN

DOI:  https://doi.org/10.1111/gtc.12902
Biomolecules. 2021 Sep 30. pii: 1439. [Epub ahead of print]11(10):

Lipid Profiles of RAS Nanoclusters Regulate RAS Function.

Yong Zhou, John F Hancock.

  The lipid-anchored RAS (Rat sarcoma) small GTPases (guanosine triphosphate hydrolases) are highly prevalent in human cancer. Traditional strategies of targeting the enzymatic activities of RAS have been shown to be difficult. Alternatively, RAS function and pathology are mostly restricted to nanoclusters on the plasma membrane (PM). Lipids are important structural components of these signaling platforms on the PM. However, how RAS nanoclusters selectively enrich distinct lipids in the PM, how different lipids contribute to RAS signaling and oncogenesis and whether the selective lipid sorting of RAS nanoclusters can be targeted have not been well-understood. Latest advances in quantitative super-resolution imaging and molecular dynamic simulations have allowed detailed characterization RAS/lipid interactions. In this review, we discuss the latest findings on the select lipid composition (with headgroup and acyl chain specificities) within RAS nanoclusters, the specific mechanisms for the select lipid sorting of RAS nanoclusters on the PM and how perturbing lipid compositions within RAS nanoclusters impacts RAS function and pathology. We also describe different strategies of manipulating lipid composition within RAS nanoclusters on the PM.

Keywords:  RAS; lipid acyl chain; nanoclusters; phosphatidylserine; phospholipids; plasma membrane

DOI:  https://doi.org/10.3390/biom11101439
Genes (Basel). 2021 Sep 29. pii: 1551. [Epub ahead of print]12(10):

YB-1 Oncoprotein Controls PI3K/Akt Pathway by Reducing Pten Protein Level.

Antonella Delicato, Eleonora Montuori, Tiziana Angrisano, Alessandra Pollice, Viola Calabrò.

  YB-1 is a multifunctional protein overexpressed in many types of cancer. It is a crucial oncoprotein that regulates cancer cell progression and proliferation. Ubiquitously expressed in human cells, YB-1 protein functions are strictly dependent on its subcellular localization. In the cytoplasm, where YB-1 is primarily localized, it regulates mRNA translation and stability. However, in response to stress stimuli and activation of PI3K and RSK signaling, YB-1 moves to the nucleus acting as a prosurvival factor. YB-1 is reported to regulate many cellular signaling pathways in different types of malignancies. Furthermore, several observations also suggest that YB-1 is a sensor of oxidative stress and DNA damage. Here we show that YB-1 reduces PTEN intracellular levels thus leading to PI3K/Akt pathway activation. Remarkably, PTEN reduction mediated by YB-1 overexpression can be observed in human immortalized keratinocytes and HEK293T cells and cannot be reversed by proteasome inhibition. Real-time PCR data indicate that YB-1 silencing up-regulates the PTEN mRNA level. Collectively, these observations indicate that YB-1 negatively controls PTEN at the transcript level and its overexpression could confer survival and proliferative advantage to PTEN proficient cancer cells.

Keywords:  PI3K/Akt pathway; PTEN; YB-1; cold-shock proteins; proteasome

DOI:  https://doi.org/10.3390/genes12101551
Int J Mol Sci. 2021 Oct 11. pii: 10964. [Epub ahead of print]22(20):

The Role of Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3 in the Pathogenesis of Human Cancer.

Chien-An Chu, Yi-Wen Wang, Yi-Lin Chen, Hui-Wen Chen, Jing-Jing Chuang, Hong-Yi Chang, Chung-Liang Ho, Chen Chang, Nan-Haw Chow, Chung-Ta Lee.

  Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3), the mammalian ortholog of yeast vesicular protein sorting 34 (Vps34), belongs to the phosphoinositide 3-kinase (PI3K) family. PIK3C3 can phosphorylate phosphatidylinositol (PtdIns) to generate phosphatidylinositol 3-phosphate (PI3P), a phospholipid central to autophagy. Inhibition of PIK3C3 successfully inhibits autophagy. Autophagy maintains cell survival when modifications occur in the cellular environment and helps tumor cells resist metabolic stress and cancer treatment. In addition, PIK3C3 could induce oncogenic transformation and enhance tumor cell proliferation, growth, and invasion through mechanisms independent of autophagy. This review addresses the structural and functional features, tissue distribution, and expression pattern of PIK3C3 in a variety of human tumors and highlights the underlying mechanisms involved in carcinogenesis. The implications in cancer biology, patient prognosis prediction, and cancer therapy are discussed. Altogether, the discovery of pharmacological inhibitors of PIK3C3 could reveal novel strategies for improving treatment outcomes for PIK3C3-mediated human diseases.

Keywords:  PIK3C3; Vps34; autophagy; cancer; colorectal cancer

DOI:  https://doi.org/10.3390/ijms222010964
Mol Biol Rep. 2021 Oct 20.

SGK1, autophagy and cancer: an overview.

Madiha Javeed Ghani.

   BACKGROUND: The serum and glucocorticoid-induced kinase-1 (SGK1) belonging to the AGC protein kinase family phosphorylates serine and threonine residues of target proteins. It regulates numerous ion channels and transporters and promotes survival under cellular stress. Unique to SGK1 is a tight control at transcriptional and post-transcriptional levels. SGK1 regulates multiple signal transduction pathways related to tumor development. Several studies have reported that SGK1 is upregulated in different types of human malignancies and induces resistance against inhibitors, drugs, and targeted therapies.
RESULTS AND CONCLUSION: This review highlights the cellular functions of SGK1, its crucial role in cancer development, and clinical insights for SGK1 targeted therapies. Furthermore, the role of SGK1-mediated autophagy as a potential therapeutic target for cancer has been discussed.

Keywords:  Autophagy; Cancer; Inhibitors; SGK1; Tumorigenesis

DOI:  https://doi.org/10.1007/s11033-021-06836-6