Deregulated G1/S control and energy stress contribute to the synthetic lethal interactions between inactivation ofRBandTSC1/TSC2

Abstract

SummarySynthetic lethality is a potential strategy for cancer treatment by specifically promoting the death of cancer cells with particular defects such as the loss of the RB (RB1) tumor suppressor. We previously showed that inactivation of both RB and TSC2 induces synergistic apoptosis during the development of Drosophila melanogaster and in cancer cells. However, the in vivo mechanism of this syntheticlethal interaction is not clear. Here, we show that synergistic cell death in tissues that have lost the RB and TSC orthologs rbf and dtsc1/ gig, respectively, or overexpress Rheb and dE2F1, are correlated with synergistic defects in G1-S control, which causes cells to accumulate DNA damage. Coexpression of the G1-S inhibitor Dap, but not the G2-M inhibitor dWee1, decreases DNA damage and reduces cell death. In addition, we show that rbf and dtsc1 mutant cells are under energy stress, are sensitive to decreased energy levels and depend on the cellular energy stress-response pathway for survival. Decreasing mitochondrial ATP synthesis by inactivating cova or abrogating the energy-stress response by removing the metabolic regulator LKB1 both enhance the elimination of cells lacking either rbf or dtsc1. These observations, in conjunction with the finding that deregulation of TORC1 induces activation of JNK, indicate that multiple cellular stresses are induced and contribute to the synthetic-lethal interactions between RB and TSC1/TSC2 inactivation. The insights gained from this study suggest new approaches for targeting RB-deficient cancers.

ESCRT-0 complex modulates Rbf-mutant cell survival by regulating Rhomboid endosomal trafficking and EGFR signaling

“…However, because stam and hrs mutants have been shown to affect the localization of a large number of receptors in different signaling pathways, the possibility that other pathways also contribute to the synergistic cell death of rbf stam double mutants cannot be excluded. Previously, mutations of axin, gig and Drosophila Tsc1 (dTsc1) have also been reported to induce synergistic cell death with rbf (Gordon et al, 2013;Hsieh et al, 2010;Li et al, 2010;Zhang et al, 2014). Interestingly, although synergistic cell death of rbf stam double-mutant cells is restricted in posterior eye discs, synergistic cell death in rbf axin, rbf gig or rbf dTsc1 double-mutant clones is more prominent in the anterior proliferating region of the eye disc.…”

“…The Drosophila developing eye provides a model system to identify genes that modulate the proliferation, differentiation or apoptosis of rbf-inactivated cells (Gordon et al, 2013;Li et al, 2010;Steele et al, 2009;Tanaka-Matakatsu et al, 2009;Zhang et al, 2014). Photoreceptor differentiation in the developing eye initiates in the morphogenetic furrow (Treisman, 2013).…”

RB1: a prototype tumor suppressor and an enigma

“…Zhu and colleagues Gordon et al 2013;Zhao et al 2013) have shown that inactivation of Skp2 can suppress proliferation of p53-and pRB-deficient cells in part through an up-regulation of p27 (Zhao et al 2015) and the activation of E2F1-mediated apoptosis (Lu et al 2014). This genetic interaction is effective at suppressing tumorigenesis in mouse models but has yet to be applied to human tumors.…”

“…This genetic interaction is effective at suppressing tumorigenesis in mouse models but has yet to be applied to human tumors. Based on genetic interactions that were discovered in Drosophila, others have suggested targeting TSC2 to elevate reactive oxygen species (ROS) in RB1 mutant tumors (Li et al 2010;Gordon et al 2013). Potentially, other metabolic features of RB1 mutant cells, such as the changes in mitochondrial activity, depletion of nucleotide pools, or changes in autophagy, might provide alternative therapeutic strategies (Angus et al 2002;Tracy et al 2007;Macleod 2008).…”

Differential control of Yorkie activity by LKB1/AMPK and the Hippo/Warts cascade in the central nervous system

“…Is the LKB1/AMPK module generally important in epithelia to restrict Yki/YAP activity? Although lkb1 mutant clones in epithelial cells generally do not overgrow (90), this may be a result of disruption of apicobasal polarity in these cells, which is a well-characterized consequence of LKB1 loss that may mask overproliferation phenotypes (74,(91)(92)(93).…”