Inhibitors of the PI3K/Akt/mTOR Pathway in Prostate Cancer Chemoprevention and Intervention
Nazanin Momeni RoudsariNaser‐Aldin LashgariSaeideh MomtazShaghayegh AbaftFatemeh JamaliPardis SafaiepourKiyana NarimisaGloria JacksonAnusha BishayeeNima RezaeiAmir Hossein AbdolghaffariAnupam Bishayee
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The phosphatidylinositol 3-kinase (PI3K)/serine-threonine kinase (Akt)/mammalian target of the rapamycin (mTOR)-signaling pathway has been suggested to have connections with the malignant transformation, growth, proliferation, and metastasis of various cancers and solid tumors. Relevant connections between the PI3K/Akt/mTOR pathway, cell survival, and prostate cancer (PC) provide a great therapeutic target for PC prevention or treatment. Recent studies have focused on small-molecule mTOR inhibitors or their usage in coordination with other therapeutics for PC treatment that are currently undergoing clinical testing. In this study, the function of the PI3K/Akt/mTOR pathway, the consequence of its dysregulation, and the development of mTOR inhibitors, either as an individual substance or in combination with other agents, and their clinical implications are discussed. The rationale for targeting the PI3K/Akt/mTOR pathway, and specifically the application and potential utility of natural agents involved in PC treatment is described. In addition to the small-molecule mTOR inhibitors, there are evidence that several natural agents are able to target the PI3K/Akt/mTOR pathway in prostatic neoplasms. These natural mTOR inhibitors can interfere with the PI3K/Akt/mTOR pathway through multiple mechanisms; however, inhibition of Akt and suppression of mTOR 1 activity are two major therapeutic approaches. Combination therapy improves the efficacy of these inhibitors to either suppress the PC progression or circumvent the resistance by cancer cells.Keywords:
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The mammalian target of rapamycin (mTOR) serine/threonine kinase is the catalytic component of two evolutionarily conserved signaling complexes. mTOR signaling complex 1 (mTORC1) is a key regulator of growth factor and nutrient signaling. S6 kinase is the best-characterized downstream effector of mTORC1. mTOR signaling complex 2 (mTORC2) has a role in regulating the actin cytoskeleton and activating Akt through S473 phosphorylation. Herein, we show that mTOR is phosphorylated differentially when associated with mTORC1 and mTORC2 and that intact complexes are required for these mTORC-specific mTOR phosphorylations. Specifically, we find that mTORC1 contains mTOR phosphorylated predominantly on S2448, whereas mTORC2 contains mTOR phosphorylated predominantly on S2481. Using S2481 phosphorylation as a marker for mTORC2 sensitivity to rapamycin, we find that mTORC2 formation is in fact rapamycin sensitive in several cancer cell lines in which it had been previously reported that mTORC2 assembly and function were rapamycin insensitive. Thus, phospho-S2481 on mTOR serves as a biomarker for intact mTORC2 and its sensitivity to rapamycin.
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The mammalian target of rapamycin (mTOR) plays a critical role in the regulation of cell growth, proliferation,and metabolism by integrating growth factor stimulation and energy/nutrient input through a complex signaling network.The mTOR kinase is a part of two structurally and functionally distinct multiple protein complexes, mTORC1 and mTORC2. The mammalian target of rapamycin complex 1 (mTORC1) is rapamycin-sensitive and mediates temporal control of cell growth by regulating several cellular processes, such as translation, transcription, and nutrient transport while the mammalian target of rapamycin complex 2 (mTORC2) is in sensitive to rapamycin and is involved in spatial control of cell growth via cytoskeleton regulation. Here we discuss the mechanism of mTOR regulation in tumor malignancy through a variety of signaling pathways and the potential of mTOR inhibitors for the treatment of cancer.
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AbstractThe mammalian target of rapamycin (mTOR) is centrally involved in growth, survival and metabolism. In cancer, mTOR is frequently hyperactivated and is a clinically validated target for drug development. Until recently, we have relied largely on the use of rapamycin to study mTOR function and its anticancer potential. Recent insights now indicate that rapamycin is a partial inhibitor of mTOR through allosteric inhibition of mTOR complex-1 (mTORC1) but not mTOR complex-2 (mTORC2). Both the mechanism of action and the cellular response to mTORC1 inhibition by rapamycin and related drugs may limit the effectiveness of these compounds as antitumor agents. We and others have recently reported the discovery of second-generation ATP-competitive mTOR kinase inhibitors (TKIs) that bind to the active sites of mTORC1 and mTORC2, thereby targeting mTOR signaling function globally (see refs. 1-4). The discovery of specific, active-site mTOR inhibitors has opened a new chapter in the 40-plus year old odyssey that began with the discovery of rapamycin from a soil sample collected on Easter Island (see Vézina C, et al. J Antibiot 1975). Here, we discuss recent studies that highlight the emergence of rapamycin-resistant mTOR function in protein synthesis, cell growth, survival and metabolism. It is shown that these rapamycin-resistant mTOR functions are profoundly inhibited by TKIs. A more complete suppression of mTOR global signaling network by the new inhibitors is expected to yield a deeper and broader antitumor response in the clinic.
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Mammalian Target of Rapamycin (mTOR) is a serine/threonine kinase and that forms two multiprotein complexes known as the mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTOR regulates cell growth, proliferation and survival. mTORC1 is composed of the mTOR catalytic subunit and three associated proteins: raptor, mLST8/$G{\beta}L$ and PRAS40. mTORC2 contains mTOR, rictor, mLST8/$G{\beta}L$ , mSin1, and protor. Here, we discuss mTOR as a promising anti-ischemic agent. It is believed that mTORC2 lies down-stream of Akt and acts as a direct activator of Akt. The different functions of mTOR can be explained by the existence of two distinct mTOR complexes containing unique interacting proteins. The loss of TSC2, which is upstream of mTOR, activates S6K1, promotes cell growth and survival, activates mTOR kinase activities, inhibits mTORC1 and mTORC2 via mTOR inhibitors, and suppresses S6K1 and Akt. Although mTOR signaling pathways are often activated in human diseases, such as cancer, mTOR signaling pathways are deactivated in ischemic diseases. From Drosophila to humans, mTOR is necessary for Ser473 phosphorylation of Akt, and the regulation of Akt-mTOR signaling pathways may have a potential role in ischemic disease. This review evaluates the potential functions of mTOR in ischemic diseases. A novel mTOR-interacting protein deregulates over-expression in ischemic disease, representing a new mechanism for controlling mTOR signaling pathways and potential therapeutic strategies for ischemic diseases.
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The mammalian target of rapamycin (mTOR) plays a central role in the regulation of cell growth. mTOR exists in two distinct complexes, mTORC1 and mTORC2. mTORC1 is known to receive inputs from multiple signaling pathways, including growth factors, nutrients, and cellular energy levels to stimulate protein synthesis by phosphorylating key translation regulators such as ribosomal S6 kinase (S6K) and eukaryote initiation factor 4E binding protein 1 (4EBP1). In contrast, mTORC2 regulates cell morphology and also phosphorylates AKT. Recent studies have established that dysregulated mTOR activity is associated with several hamartoma syndromes and metabolic disorders. The mechanism of mTOR regulation by numerous intracellular signaling pathways and the function of mTOR in physiological regulation will be discussed.
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Abstract Nematode EAK-7 (enhancer-of-akt-1-7) regulates dauer formation and controls life span; however, the function of the human ortholog mammalian EAK-7 (mEAK-7) is unknown. We report that mEAK-7 activates an alternative mechanistic/mammalian target of rapamycin (mTOR) signaling pathway in human cells, in which mEAK-7 interacts with mTOR at the lysosome to facilitate S6K2 activation and 4E-BP1 repression. Despite interacting with mTOR and mammalian lethal with SEC13 protein 8 (mLST8), mEAK-7 does not interact with other mTOR complex 1 (mTORC1) or mTOR complex 2 (mTORC2) components; however, it is essential for mTOR signaling at the lysosome. This phenomenon is distinguished by S6 and 4E-BP1 activity in response to nutrient stimulation. Conventional S6K1 phosphorylation is uncoupled from S6 phosphorylation in response to mEAK-7 knockdown. mEAK-7 recruits mTOR to the lysosome, a crucial compartment for mTOR activation. Loss of mEAK-7 results in a marked decrease in lysosomal localization of mTOR, whereas overexpression of mEAK-7 results in enhanced lysosomal localization of mTOR. Deletion of the carboxyl terminus of mEAK-7 significantly decreases mTOR interaction. mEAK-7 knockdown decreases cell proliferation and migration, whereas overexpression of mEAK-7 enhances these cellular effects. Constitutively activated S6K rescues mTOR signaling in mEAK-7–knocked down cells. Thus, mEAK-7 activates an alternative mTOR signaling pathway through S6K2 and 4E-BP1 to regulate cell proliferation and migration. Citation Format: Joe T. Nguyen, Connor Ray, Alexandra L Fox, Daniela B Mendonca, Jin Koo Kim, Paul H. Krebsbach. Mammalian EAK-7 activates alternative mTOR signaling to regulate cell proliferation and migration [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr A13.
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It has been shown that mammalian target of rapamycin (mTOR) inhibitors activate Akt while inhibiting mTOR signaling. However, the underlying mechanisms and the effect of the Akt activation on mTOR-targeted cancer therapy are unclear. The present work focused on addressing the role of mTOR/rictor in mTOR inhibitor-induced Akt activation and the effect of sustained Akt activation on mTOR-targeted cancer therapy. Thus, we have shown that mTOR inhibitors increase Akt phosphorylation through a mechanism independent of mTOR/rictor because the assembly of mTOR/rictor was inhibited by mTOR inhibitors and the silencing of rictor did not abrogate mTOR inhibitor-induced Akt activation. Moreover, Akt activation during mTOR inhibition is tightly associated with development of cell resistance to mTOR inhibitors. Accordingly, cotargeting mTOR and phosphatidylinositol 3-kinase/Akt signaling prevents mTOR inhibition-initiated Akt activation and enhances antitumor effects both in cell cultures and in animal xenograft models, suggesting an effective cancer therapeutic strategy. Collectively, we conclude that inhibition of the mTOR/raptor complex initiates Akt activation independent of mTOR/rictor. Consequently, the sustained Akt activation during mTOR inhibition will counteract the anticancer efficacy of the mTOR inhibitors.
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mTOR is a serine/threonine protein kinase that has been shown to be a key player in
the regulation of cell growth and proliferation. Furthermore, mTOR forms the
catalytic core of two known mTOR complexes, mTORC1 and mTORC2. These
complexes sense various intra and extracellular signals, and regulate cellular
processes that are critical for cell growth and proliferation. However, when
conventional mTOR signalling is deregulated, cellular homeostasis is disrupted,
resulting in a wide range of human diseases such as diabetes, neurodegeneration and
cancer. Due to its involvement in tumorigenesis, mTOR has attracted enormous
interest as a therapeutic target. Initially, the classical mTOR inhibitor rapamycin was
tested as a potential treatment. However, when the compound was assessed in clinical
trials, it proved to be of limited efficacy. This led to the design of novel types of
inhibitors, which are currently being evaluated. The results obtained with rapamycin
clearly indicated that our understanding of the mTOR signalling pathway is far from
complete.
In addition, mTOR is currently known to exist in two isoforms, which are
generated by alternative splicing of the transcript. These are known as mTORα and
mTORβ respectively. The mTORα protein was the first isoform discovered and is
2,549 residues long. mTORβ is approximately one third of the length at 706 amino
acids. Both proteins share identical C-terminal domains, but mTORβ lacks the Nterminal
HEAT and FAT repeats that mTORα possesses. Work done in our lab has
shown that mTORβ is capable of forming complexes with Raptor and Rictor, which
are the key components of mTORC1 and mTORC2. Furthermore, overexpression of
mTORβ transforms immortal cells and causes tumour formation in nude mice. It is thought that modulation of cell proliferation via the mTOR signalling pathway could
be achieved through mTORβ, which behaves as a protooncogene. Thus, mTORβ has
the potential to be used as a target for anti-cancer therapies.
The first chapter of my thesis consisted of comparative modelling of
mTORβ’s C-terminal region from the FRB domain to the kinase domain. The model
that was generated could then be used to give us insight into potential mechanisms for
the inhibition of mTOR by either rapamycin or ATP-competitive inhibitors.
The second chapter examined the effects of two different mutations in
mTOR’s kinase domain on its activity. A point mutation (S2215Y) and a deletion of
12 amino acids (12del) were introduced into the kinase domain of mTORβ. Mutant
proteins were expressed in HEK293 mammalian cells and the phosphorylation status
of various mTOR substrates was assessed under different experimental conditions.
The final chapter of my thesis described how a TAP-tag fusion protein was
created. This would have been used to search for novel mTORβ binding partners in
mammalian cells had I chosen to complete my PhD studies.
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Abstract Current knowledge indicates that mTOR functions as two complexes, mTORC1 and mTORC2, in mammalian cells. mTORC1 comprises mTOR, mLST8 and raptor, and is sensitive to acute rapamycin treatment, whereas mTORC2 consists of mTOR, mLST8, rictor, mSin1 and Protor, and is sensitive to chronic rapamycin treatment in some cases. It is well known that mTORC1 phosphorylates 4E-BP1 and S6K1, while mTORC2 phosphorylates Akt and SGK1. Recently, we and others have observed that rapamycin inhibits the phosphorylation of mSin1. However, little is known about the molecular mechanism by which rapamycin inhibits mSin1 phosphorylation. Here we show that rapamycin inhibits mSin1 phosphorylation in mTOR kinase dependent manner. This is strongly supported by the findings that expression of rapamycin-resistant mTOR (mTOR-T), but not rapamycin-resistant and kinase dead mTOR (mTOR-TE) prevented rapamycin from inhibiting mSin1 phosphorylation; Knockdown of mTOR inhibited mSin1 phosphorylation. However, surprisingly, disruption of either mTORC1 or mTORC2 (by silencing raptor and rictor, respectively) failed to inhibit the phosphorylation of mSin1 as rapamycin did. Similarly, downregulation of S6K1 or Akt did not inhibit mSin1 phosphorylation as rapamycin did either. Of interest, knockdown of mLST8, a component shared by mTORC1/2, inhibited mSin1 phosphorylation. Furthermore, rapamycin treatment reduced the physical interaction of mSin1 with mLST8 and mTOR, but not with rictor. The results suggest that rapamycin inhibits mSin1 phosphorylation, which is not by inhibiting mTORC1 or mTORC2, but via inhibiting a new mTOR complex, which contains at least mTOR and mLST8. (Supported by the FWCC, LSU Health Sciences Center) Citation Format: Shile Huang, Yan Luo, Lei Liu. Rapamycin inhibits the phosphorylation of mSin1 by targeting a new mTOR complex. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4621.
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