mTOR, metabolism, and cancer
By: by Andrew Yoon Choo
Published: 2009
Language: eng
Number of pages: 269
Description: In order to maintain hometostasis, cells interpret and coordinate responses to diverse environmental cues such as growth factors, energy status, and the availability of glucose and other nutrient sources. Mutations in the pathways that coordinate these responses can contribute to metabolic or inflammatory disorders and often promote tumorigenesis. One such pathway is the m ammalian T arget o f R apamycin complex 1 (mTORC1) pathway, whose activity is tightly controlled by numerous oncogenes and tumor suppressors and is deregulated in many cancers. Therefore, rapamycin, which allosterically inhibits mTORC1, is currently being evaluated as an anti-cancer agent. However, early clinical data suggest that many tumors are refractory to rapamycin's cytostatic effects, mandating the identification of potential resistance mechanisms as well as other novel methods to target mTORC1-activated cancers. My thesis attempts to tackle both of these issues by studying the effects of long-term rapamycin treatment and the biological requirements and consequences of mTORC1 hyperactivation by using biochemical, genetic, and cell biological approaches.

First, my thesis will show that rapamycin differentially inhibits mTORC1's substrates leading to cell-type-specific effects on mRNA translation. The consequence of this differential inhibition of mTORC1's substrates was that cap-dependent translation recovered despite apparent S6K1 inhibition. Second, my thesis will show that mTORC1 is a critical regulator of metabolic supply and demand, and cells that fail to inhibit mTORC1 during energetic stress succumb to death due to the failure of oxidative phosphorylation to meet the cell's bioenergetic demand. Accordingly, I will show that EGCG, an anti-cancer compound that is currently being tested in the clinic, synergizes with DNA alkylating agents to kill TSC2-/- cells. Finally, my thesis will conclude by showing that the TCA cycle, which allocates nutrients for macromolecule production, is critical for mTORC1 activation through AMPK - and TSC2 -independent mechanisms.
Notes: "May 2009."

Thesis (Ph.D., Division of Medical Sciences (Cell and Developmental Biology))--Harvard University, 2009.

Includes bibliographical references.