mTOR as a Potential Target for the Treatment of Microbial Infections, Inflammatory Bowel Diseases, and Colorectal Cancer

Abstract

The mammalian target of rapamycin (mTOR) is the major controller of a number of important cellular activities, including protein synthesis, cell expansion, multiplication, autophagy, lysosomal function, and cellular metabolism. When mTOR interacts with specific adaptor proteins, it forms two complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The mTOR signaling system regulates gene transcription and protein manufacturing to control proliferation of cell, differentiation of immune cell, and tumor metabolism. Due to its vital role in case of microbial infections, inflammations and cancer development and progression, mTOR has been considered as a key therapeutic target for the development of targeted medication. As autophagy dysfunction is linked to changes in both innate and adaptive immune responses, bacterial clearance defects, and goblet and Paneth cell malfunction, all of these changes are linked to inflammatory bowel diseases (IBD) and colorectal cancer (CRC) pathogenesis. Preclinical and clinical data have shown that the inhibition and induction of autophagy have significant potential to be translated into the clinical applications. In IBD and several CRC models, mTORC1 inhibitors have been found effective. In the recent years, a number of novel mTOR inhibitors have been investigated in clinical trials, and a number of drugs have shown considerably enhanced efficacy when combined with mTOR inhibitors. The future developments in the mTOR targeting medications can benefit patients in individualized therapy. Advanced and innovative medicines that are more effective and have lower drug resistance are still in high demand. New findings could be relevant in medicine development, pharmacological modification, or future mTOR inhibitor research. Therefore, the goal of this review is to present a comprehensive account of current developments on the mTOR pathway and its inhibitors, with an emphasis on the management of microbial infections, the treatment of inflammatory bowel disease, and the management of colon cancer.

Keywords: colorectal cancer (CRC); inflammatory bowel diseases (IBD); mammalian target of rapamycin (mTOR).

Figure 1

The structural components, types, and physiological role of mTOR signaling pathway. Upward and downward direction of arrows indicate the increase or decrease of process or substance. When growth factor stimulates TRK receptor then it triggers the downregulation of Ras, Raf Mek, Erk, IRS, P13k, PIR3, and Akt which ultimately cause inhibition of TSC1/TSC2 complex which ultimately inhibits lysosome biogenesis autophagy and upregulates the process of ribosome/mitochondria biogenesis and lipid/protein/nucleotide synthesis and energy metabolism by inhibiting Rheb. On the other hand, Rag A/B and Rag C/D cause the same effect by amino acids upregulation.

Figure 2

mTOR inhibitors of therapeutic importance.

Figure 3

Activation of the mTOR pathway and its potential role in the targeting of microbial infections. Microbial interaction with TLRs activates the P13K > PDK > AKT > mTOR cascade, which results in mTOR activation. It promotes protein translation and the production of iNOS and interferons by phosphorylating 4E-BP1/2 (eukaryotic translation initiation factor 4E binding protein 1 and 2). Microbial detection also promotes autophagy by causing the expression of beta-defensin 2 and cathelicidin. Because mTOR inhibitor is an autophagy inhibitor, it can promote autophagy and fight microbial infections.

Figure 4

A comparative analysis of adenoma epithelial cell with defective antigen-presenting cells, role of beta-catenin, and rapamycin in the induction and control of cancer respectively. Beta-catenin and rapamycin inhibited cell growth and development of tumor induced by Wnt by inhibiting mTOR signalling.