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Abstract
The Target of Rapamycin complex 1 (TORC1) is an evolutionarily conserved kinase complex coordinating cellular growth with nutritional conditions and growth factor signaling, and its activity is elevated in many cancer types. The use of TORC1 inhibitors as anticancer drugs is, however, limited by unwanted side-effects and development of resistance. We therefore attempted to identify limiting modulators or downstream effectors of TORC1 that could serve as therapeutic targets. Drosophila epithelial tissues that lack the tumor suppressor Pten hyperproliferate upon nutrient restriction in a TORC1-dependent manner. We probed candidates of the TORC1 signaling network for factors limiting the overgrowth of Pten mutant tissues. The serine/arginine-rich splicing factor 2 (SF2) was identified as the most limiting factor: SF2 knockdown drives Pten mutant cells into apoptosis, while not affecting control tissue. SF2 acts downstream of or in parallel to TORC1 but is not required for the activation of the TORC1 target S6K. Transcriptomics analysis revealed transcripts with alternatively used exons regulated by SF2 in the tumor context, including p53. SF2 may therefore represent a highly specific therapeutic target for tumors with hyperactive TORC1 signaling.
Highlights
Target of Rapamycin complex 1 (TORC1) integrates inputs such as growth factor signaling and nutritional status with cellular growth
The TORC1 signaling network has been substantially expanded by recent research, providing numerous potential targets for therapeutic intervention in cancers with elevated TORC1 activity
We have exploited the genetically amenable model organism Drosophila to identify TORC1 signaling network members that are limiting in a model of early tumorigenesis
Summary
Target of Rapamycin complex 1 (TORC1) integrates inputs such as growth factor signaling and nutritional status with cellular growth. It functions as a downstream effector of the key oncogenic pathways PI3K/AKT and Ras/MAPK. Attenuation of TORC1 activity as a means to combat cancer has been widely explored by the use of TORC1 inhibitors such as rapamycin and rapamycin-based analogs (rapalogs) [5]. The efficacy of such treatments has been limited by the complexity of the TORC1 signaling network. A negative feedback loop from the TORC1 downstream target S6K attenuates PI3K signaling upon TORC1 activation [6,7]. High-throughput technologies enabled a significant expansion of the TORC1 signaling network by generating vast datasets of novel
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