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mTOR Signaling and Cancer Progression

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All eukaryotic cells must regulate their growth depending on the cues from their environment.

Certain genes, such as the mechanistic target of rapamycin, or mTOR, respond to various factors to regulate fundamental cellular processes, including the availability of nutrients, growth factors, and cellular stress.

mTOR is a large protein kinase of mammalian cells that exists in two functionally distinct multiprotein complexes - mTOR complex 1 or mTORC1 and mTOR complex 2 or mTORC2.

Amongst an immensely complex mTOR signaling network, the PI(3)K/AKT/mTOR pathway plays a crucial role in cell growth control.

Upon stimulation by binding insulin or insulin-like growth factors, the receptor tyrosine kinases on the cell surface activate the downstream signaling molecule- phosphatidylinositol 3-kinase or PI(3)K.

Active PI(3)K generates phosphatidylinositol 3,4,5-trisphosphate or PIP3, which enables 3-phosphoinositide-dependent kinase 1 or PDK1 to phosphorylate and activate another protein called AKT.

Active AKT protein, in turn, phosphorylates and inhibits the activity of the growth-suppressing, tuberin-hamartin complex or TSC complex.

TSC complex has a GTPase-activating activity. In its active state, it converts RHEB, a lysosomal membrane-bound protein, from an active to inactive state, therefore keeping mTORC1 in its inactive state.

When AKT inactivates the TSC complex, RHEB can remain in an active GTP-bound state. The active RHEB can further activate mTORC1.

Active mTORC1 supports cell growth and proliferation by upregulating biosynthesis of macromolecules, such as proteins and lipids, and downregulating autophagy.

Because of its key role in cell growth and metabolism, cancer cells often exploit the mTOR signaling pathway to facilitate the sustained growth of tumor cells. Therefore, the genes in the mTOR signaling pathways are commonly found to be mutated in human cancers.

Such mutations lead to abnormal activation of the mTOR pathway even in the absence of any appropriate signals.

As a result, cancer cells exploiting this pathway can evade autophagy and synthesize more proteins and lipids to support early tumor progression.

Overview

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The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.

The mTOR pathway or the PI3K/AKT/mTOR signaling pathway begins with the growth-factor-induced phosphorylation of a specific cell-surface receptor. The phosphorylated receptor transmits signals that result in the activation of downstream protein kinases— PI3K, Akt, and mTOR complex 1 or mTORC1.

Upon activation, mTORC1 upregulates protein synthesis mainly through the phosphorylation of the eukaryotic initiation factor 4E-binding protein 1 or 4EBP1 and the p70 ribosomal S6 kinase 1 or S6K1. Via activation of S6K1, mTORC1 also regulates the activity of transcription factor - sterol responsive element binding protein or SREBP, which further regulates the synthesis of lipids in a growing cell. In addition, S6K1 is also involved in the activation of carbamoyl-phosphate synthetase (CAD), which plays a critical role in the de novo pyrimidine synthesis pathway.

Besides synthesis of the macromolecules, mTORC1 has also been shown to regulate mitochondrial metabolism and biosynthesis. It facilitates tumor cell growth by shifting glucose metabolism to glycolysis instead of oxidative phosphorylation, a process called the Warburg effect, to help the tumor cells generate the energy needed for their rapid growth and proliferation.

In the absence of essential nutrients, cells activate autophagy to supply basic components such as amino acids to the cellular machinery. Inhibition of mTORC1 has been shown to increase autophagy, whereas stimulation of mTORC1 reduces autophagy.

Due to its varied roles in cellular functions, deregulation in mTOR signaling has not only been implicated in the progression of cancer but also several other diseases, including, aging and diabetes.

Transcript

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All eukaryotic cells must regulate their growth depending on the cues from their environment.

Certain genes, such as the mechanistic target of rapamycin, or mTOR, respond to various factors to regulate fundamental cellular processes, including the availability of nutrients, growth factors, and cellular stress.

mTOR is a large protein kinase of mammalian cells that exists in two functionally distinct multiprotein complexes - mTOR complex 1 or mTORC1 and mTOR complex 2 or mTORC2.

Amongst an immensely complex mTOR signaling network, the PI(3)K/AKT/mTOR pathway plays a crucial role in cell growth control.

Upon stimulation by binding insulin or insulin-like growth factors, the receptor tyrosine kinases on the cell surface activate the downstream signaling molecule- phosphatidylinositol 3-kinase or PI(3)K.

Active PI(3)K generates phosphatidylinositol 3,4,5-trisphosphate or PIP3, which enables 3-phosphoinositide-dependent kinase 1 or PDK1 to phosphorylate and activate another protein called AKT.

Active AKT protein, in turn, phosphorylates and inhibits the activity of the growth-suppressing, tuberin-hamartin complex or TSC complex.

TSC complex has a GTPase-activating activity. In its active state, it converts RHEB, a lysosomal membrane-bound protein, from an active to inactive state, therefore keeping mTORC1 in its inactive state.

When AKT inactivates the TSC complex, RHEB can remain in an active GTP-bound state. The active RHEB can further activate mTORC1.

Active mTORC1 supports cell growth and proliferation by upregulating biosynthesis of macromolecules, such as proteins and lipids, and downregulating autophagy.

Because of its key role in cell growth and metabolism, cancer cells often exploit the mTOR signaling pathway to facilitate the sustained growth of tumor cells. Therefore, the genes in the mTOR signaling pathways are commonly found to be mutated in human cancers.

Such mutations lead to abnormal activation of the mTOR pathway even in the absence of any appropriate signals.

As a result, cancer cells exploiting this pathway can evade autophagy and synthesize more proteins and lipids to support early tumor progression.

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