The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

Abstract

The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

Metabolic stress regulates cytoskeletal dynamics and metastasis of cancer cells

“…Despite the ambivalent nature of autophagy in tumor progression (17), there is now considerable effort to target the regulators of this pathway for cancer therapy. Our data highlight the complexity of this approach and suggest that disabling autophagy-initiating molecules, in particular ULK1, may have detrimental contraindications, not only by removing to tumor suppression (40) or, conversely, cell survival under metabolic stress (41) or tumor adaptation (18). Our results show that AMPK activation, while potentially important for cell survival (41), also provides a strong barrier against tumor cell motility and metastasis in a pathway reversed by mTORC1 activation (15).…”

Metformin inhibits growth of eutopic stromal cells from adenomyotic endometrium via AMPK activation and subsequent inhibition of AKT phosphorylation: a possible role in the treatment of adenomyosis

“…AMPK signaling is also linked to the PI3K pathway (Tao et al 2010), which is an important regulator of cell survival (Chen et al 2010). AMPK signaling has, therefore, been investigated as a potential therapeutic target for the treatment of diseases with aberrantly activated PI3K signaling, such as carcinomas (van Veelen et al 2011, Carling et al 2012, Martelli et al 2012. To date, however, to our knowledge no studies have investigated whether AMPK may play a role in adenomyosis.…”

Two novel STK11 missense mutations induce phosphorylation of S6K and promote cell proliferation in Peutz‑Jeghers syndrome

“…Furthermore, activation of mTORC1 inhibits autophagy via phosphorylation of autophagy-related protein 13 and ULK1/2 (44). Rapamycin, a specific mTOR inhibitor, has been developed as an effective drug for the treatment of PJS and its associated tumors (22,45).…”

“…Therefore, mutations in STK11 that inactivate its endogenous activity can negatively regulate mTORC1 signaling, resulting in phosphorylation and activation of its downstream targets. In turn, this is able to relieve inhibition on protein synthesis, and promote cell growth and tumorigenesis (20)(21)(22).…”