Mohamed Elgendy, PhD

Mohamed Elgendy, PhD

E-Mail: mohamed.elgendy@univie.ac.at 

Department of Pharmaceutical Chemistry

Project: "RAT - Role of Atf4 in Tumorigenesis" - Investigation of the roles of Activating Transcription Factor 4 (ATF4) in Ras-induced tumorigenesis

Activating mutations in genes that drive cell proliferation are required but not sufficient on their own to give rise to cancer as they typically require other co-transforming mutations. The reason is that mammalian cells are equipped with mechanisms that sense apparent growth signals that could lead to transforming cells into a tumorigenic threat to the organism. Those mechanisms sense such uncontrolled growth signals and coordinate the activation of responses such as cell cycle arrest, senescence or cell death (suicide) that aim to eliminate the threat. Only when such responses are disabled by other co-transforming mutations, can transformation occur.

Ras are important oncoproteins found mutated in 25-30% of all human tumors (Fernández-Medarde et al., 2011). Ras shuffle between active and inactive status and regulate several signalling pathways that control growth and proliferation. In an attempt to understand how cells react to increased activity of H-Ras, my previous work has shown that cells respond to mutational activation of H-Ras by triggering massive autophagy which seems to act as a fail-safe mechanism to restrain tumorigenesis (Elgendy et al., 2011). H-Ras-induced autophagy was associated with the induction of Beclin 1 and Noxa, which all act in the same pathway to mediate autophagy induction. To get further insight into how Ras mechanistically leads to the induction of Beclin 1 and Noxa and to dissect this pathway further, I used pharmacological inhibitors of several pathways downstream of Ras. Inhibition of the MEK/ERK pathway completely abolished Ras-induced Beclin 1 and Noxa expression. Taking that further, I used siRNA to knockdown several known factors that act downstream of ERK. My unpublished observations show that ablation of ATF4 (and to much less extent c-jun) completely abolishes the induction of Beclin 1 and Noxa. Since ATF4 is known to be an essential mediator of ER stress (Szegezdi et al., 2006) and given that ER stress has been shown to mediate the induction of autophagy in several contexts, I assessed the effect of ATF4 knockdown on Ras-induced autophagy. Ablation of ATF4 abrogated Ras-induced autophagy as assessed by percentage of cells showing LC3 puncta, a widely used marker of autophagy (Klionsky et al., 2014). These results indicate that ATF4 acts as the master regulator of the responses triggered by mutational activation of H-Ras. This proposal aims to dissect the interplay between ATF4 and H-Ras, to further explore whether ATF4 controls other mediators besides Beclin 1 and Noxa, and how it co-ordinates the whole ER stress-autophagy response to ultimately understand the implications for H-Ras-driven tumorigenesis.

Publications

  • Abdel-Aziz A.K., Abdel-Naim A.B., Shouman S., Minucci S., Elgendy M*. From Resistance to Sensitivity: Insights and Implications of Biphasic Modulation of Autophagy by Sunitinib. Front Pharmacol. 2017 Oct 10;8:718. doi: 10.3389/fphar.2017.00718. eCollection 2017.

  • Elgendy M. Assessment of Modulation of Protein Stability Using Pulse-chase Method. Bio Protocol 2017 Vol 7, Iss 16. 10.21769/BioProtoc.2443.
  • Ferrari E., Bruhn C., Peretti M., Cassani C., Carotenuto W.V., Elgendy M., Shubassi G., Lucca C., Bermejo R., Varasi M., Minucci S., Longhese M.P., Foiani M. PP2A Controls Genome Integrity by Integrating Nutrient-Sensing and Metabolic Pathways with the DNA Damage Response. Mol Cell. 2017 Jun 12. S1097-2765(17)30367-2.
  • Elgendy M. The yin yang of sunitinib: One drug, two doses, and multiple outcomes. Mol Cell Oncol. 2017 Feb 23;4(2):e1285385. doi: 10.1080/23723556.2017.1285385. eCollection 2017.
  • Elgendy M., Abdel-Aziz, A. K., Renne, S.L., Bornaghi, V., Procopio, G., Colecchia, M., Kanesvaran, R., Toh, C. K., Bossi, D., Pallavicini, I., Perez-Gracia, J. L., Lozano, M.D., Giandomenico, V., Mercurio, C., Lanfrancone, L., Fazio, N., Nole, F., Teh, B. T. Renne, G., Minucci, S. Dual modulation of MCL-1 and mTOR determines the response to sunitinib. J Clin Invest. 2017;127(1):153-168. doi:10.1172/JCI84386.
  • Elgendy M. and Minucci S., Autophagy-independent role of Beclin 1 in promoting Mcl-1 degradation contributes to its tumor suppressor effect. 2015 Autophagy 11:3, 581-582
  • Elgendy M., Ciro M., Saad Eldin A., Belmonte G., Dal Zuffo R., Mirraco C., Mercurio C., Lanfrancone L., Foiani M and Minucci S. Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner.2014 Nature Comm. 5:5637. doi: 10.1038/ncomms6637
  • Elgendy M., Sheridan C., Brumati G. and Martin S.J. Oncogenic Ras-Induced Expression of Noxa and Beclin-1 Promotes Autophagic Cell Death and Limits Clonogenic Survival. 2011 Molecular Cell 42(1), 23 – 35
  • Cella C.A., Minucci S., Spada F., Galdy S., Elgendy M., Ravenda S. P. , Zampino, M. G and Fazio N. Dual inhibition of mTOR pathway and VEGF signalling in neuroendocrine neoplasms: from bench to bedside.2015 Cancer Treat. Rev.  41:754–760
  • Girgis AS, Panda SS, Srour AM, Farag H, Ismail NS, Elgendy M, Abdel-Aziz AK, Katritzky AR Rational design, synthesis and molecular modeling studies of novel anti-oncological alkaloids against melanoma. 2015 Org. Biomol. Chem 13, 6619-6633
  • Abdel-Aziz AK, Shouman S, El-Demerdasha E, Elgendy M and Abdel-Naim AB. Chloroquine synergizes sunitinib cytotoxicity via modulating autophagic, apoptotic and angiogenic machineries. 2014 Chemico-Biological Interactions. 217: 28–40
  • Handoussa H., Hanafi R., Eddiasty I., Elgendy M., Linscheid M., Mahran L., Ayoub N. In Vitro  and In Vivo Anti-Inflammatory and Cytotoxic Capacities of Dietary Phenolics Isolated From Corchorus Olitorius and Vitis Vinifera , 2013 Journal of Functional Foods 5(3):1204-1216
  • Klionsky D.J.,…, Elgendy M., et al. Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy. 2012 Autophagy 4, 445-544.
  • Brumati G., Sheridan C., Elgendy M., Brunet M. and Martin S.J. An ERK-dependent pathway to Noxa expression regulates apoptosis by platinum-based chemotherapeutic drugs. 2010.  Oncogene 29, 6428-6441
  • Logue S., Elgendy M. and Martin S.J. Expression, purification and use of recombinant annexin V for the detection of apoptotic cell. 2009 Nature Protoc. 4, 1383 - 1395
  • Elgendy M., Abdel-Aziz A.K., Bornaghi V., Renne S.L., Giandomenico V., Renne G., Mercurio C., Fazio N., Nole F., Minucci S.. Dual modulation of Mcl-1 and mTOR by sunitinib determines sensitivity or resistance of cancer cells. In revision Journal of Clinical Investigation
  • Elgendy M., Abdel-Aziz A.K., Bornaghi V., Belmonte G., Dal Zuffo R., Mirraco C. and Minucci S. Mcl-1 binds mTOR and modulates mTORC1 and mTORC2 signaling to promot proliferation. Submitted