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mTOR-Rictor-EGFR axis in oncogenesis and diagnosis of glioblastoma multiforme

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Glioblastoma multiforme (GBM) is one of the aggressive brain cancers with patients having less survival period upto 12–15 months. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase, belongs to the phosphatidylinositol 3-kinases (PI3K) pathway and is involved in various cellular processes of cancer cells. Cancer metabolism is regulated by mTOR and its components. mTOR forms two complexes as mTORC1 and mTORC2. Studies have identified the key component of the mTORC2 complex, Rapamycin-insensitive companion of mammalian target of rapamycin (Rictor) plays a prominent role in the regulation of cancer cell proliferation and metabolism. Apart, growth factor receptor signaling such as epidermal growth factor signaling mediated by epidermal growth factor receptor (EGFR) regulates cancer-related processes. In EGFR signaling various other signaling cascades such as phosphatidyl-inositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR pathway) and Ras/Raf/mitogen-activated protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) -dependent signaling cross-talk each other. From various studies about GBM, it is very well established that Rictor and EGFR mediated signaling pathways majorly playing a pivotal role in chemoresistance and tumor aggressiveness. Recent studies have shown that non-coding RNAs such as microRNAs (miRs) and long non-coding RNAs (lncRNAs) regulate the EGFR and Rictor and sensitize the cells towards chemotherapeutic agents. Thus, understanding of microRNA mediated regulation of EGFR and Rictor will help in cancer prevention and management as well as a future therapy.

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Funding

This work was supported by SERB, Government of INDIA with Grant Number EMR/2017/001201. I would like to thank SASTRA management for infrastructural support and constant encouragement.

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  1. Functional Genomics and Disease Biology Laboratory, School of Chemical and Biotechnology (SCBT), SASTRA Deemed University, Tirumalaisamudram, Thanjavur, 613401, Tamil Nadu, India

    M. Janaki Ramaiah & K. Rohil Kumar

  2. School of Chemical and Biotechnology (SCBT), SASTRA Deemed University, Tirumalaisamudram, Thanjavur, 613401, Tamil Nadu, India

    M. Janaki Ramaiah

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Correspondence to M. Janaki Ramaiah.

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Supplementary file1—Supplementary Figure 1. Glucose and acetate dependent Rictor activation and GBM cancer cell proliferation. Glucose and acetate metabolism provide acetyl-CoA in GBM cancer cells. The histone acetyl -transferases (HATs) CBP/ p300 and GCNF/PCAF acetylates various lysine residues such as K1107, K1108, K1116, K1119, K1125 on Rictor protein leading to enhanced mTORC2 activity. The increased mTORC2 phosphorylates Akt at Ser 473. IGF-IGFR pathway brings Akt, 3’-phosphoinositide-dependent kinase-1 (PDK1) proteins to the plasma membrane. Here PDK1 phosphorylates Akt at T308 and Rictor driven mTORC2 activity induce phosphorylate Akt Ser-473 in response to IGF-1 stimulation. Thus, the IGF pathway is involved in Akt activation, cell growth, survival, and proliferation. (JPG 160 kb)

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Supplementary file2—Supplementary Figure 2. The production of acetyl COA and its function at oligodendrocytes. Glucose and acetate are the sources of acetyl COA production. The acetyl COA combine with the oxaloacetate form citrate. The citrate with the help of enzyme citrate lyase will be cleaved into acetate in the mitochondria. The acetyl -COA combine with aspartate to form N-acetyl aspartate (NAA) and will be transported from its place of production (i, e, mitochondria of brain adipocyte) to oligodendrocyte where in NAA will be further utilized for various biological processes. (JPG 60 kb)

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Supplementary file3—Supplementary Figure 3. Synthesis of N-acetyl aspartate (NAA) and NAAG. In neurons particularly at mitochondria of brain adipocytes, the L-aspartate and acetyl-COA combine and form N-acetyl aspartate (NAA) and transported to oligodendrocytes wherein NAA will be converted back to L-aspartate and acetyl-COA (or) NAA combine with glutamate and form N-acetyl aspartate glutamate (NAAG). From neurons, the NAAG will be transported into extracellular space wherein the action of enzyme carboxypeptidase NAAG will be converted to NAA and glutamate. (JPG 44 kb)

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Supplementary file4—Supplementary Figure 4. PKC protein interconnects EGFR and PI3K/Akt/mTOR pathways. The activated EGFR interconnect with the mTOR pathway Via PKC protein. Thus, the possibility of EGFR regulating the mTOR pathway which involved in cancer cell growth and proliferation. (TIF 666 kb)

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Supplementary file5—Supplementary Figure 5. mTORC1 and mTORC2 complexes and their role in cancer cell. mTORC1 complex consists of mTOR, mLST8, DEPTOR, RAPTOR, PRAS40, FKBP38. Where as mTORC2 complex comprises of mTOR, mLST8, DEPTOR, RICTOR, mSIN1, Protor1/2. Here mTORC1 mainly participate in protein synthesis, microRNA biogenesis and cell growth. mTORC2 complex participate in cancer cell metabolism, survival and drug-resistance. (JPG 272 kb)

Supplementary file6 (DOCX 15 kb)

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Ramaiah, M.J., Kumar, K.R. mTOR-Rictor-EGFR axis in oncogenesis and diagnosis of glioblastoma multiforme. Mol Biol Rep 48, 4813–4835 (2021). https://doi.org/10.1007/s11033-021-06462-2

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  1. M. Janaki Ramaiah View author profile