DEVON MICHAEL IVY

PhD Graduate

PhD program:: XXXVI


supervisor: Prof. Gianluca Canettieri

Thesis title: The MYC 5’ upstream region facilitates autophagic adaptations in response to PI3K inhibition

The internal ribosome entry site (IRES) is considered one of the mechanisms in which colorectal cancer cells can utilize to survive the stresses of the tumor microenvironment and to escape cell death. The proto-oncogene MYC is upregulated in 70% of human neoplasia and considered a a key driver of colorectal cancer (CRC). An IRES was discovered in its 5’ UTR, presenting the possibility of tumoral cells utilizing this mechanism to sustain cell growth under stressful conditions. However, controversy exists surrounding the technical approaches used to validate this sequence. We investigated the involvement of the MYC IRES in a wide range of cellular stresses using a CRIPS-Cas9 approach to excise the sequence from CRC cell lines. Our results demonstrate that the MYC IRES does not facilitate cap-independent translation. Rather, it appears to function as transcriptional enhancer responsive to PI3K signaling mediated through the MAP-kinase pathway. CRC cells adapt to survive PI3K inhibition by increasing the autophagic flux, however, those cells lacking the IRES fail to do so, and demonstrate antiproliferative sensitivity. This sensitivity is also found in Burkitt Lymphoma (BL) cells that exhibit a MYC translocation dissociating the IRES from the coding sequence. In conclusion, we find that the MYC IRES functions not to facilitate internal ribosome entry, but to enhance MYC transcription in response to PI3K inhibition in order to promote cancer cell survival though increased autophagic flux.

Research products

11573/1721584 - 2024 - MYC upstream region orchestrates resistance to PI3K inhibitors in cancer cells through FOXO3a-mediated autophagic adaptation
Bordone, Rosa; Ivy, Devon Michael; D'amico, Rodrigo; Barba, Martina; Gaggianesi, Miriam; Di Pastena, Fiorella; Cesaro, Bianca; Bufalieri, Francesca; Balzerano, Alessio; De Smaele, Enrico; Giannini, Giuseppe; Di Marcotullio, Lucia; Fatica, Alessandro; Stassi, Giorgio; Di Magno, Laura; Coni, Sonia; Canettieri, Gianluca - 01a Articolo in rivista
paper: ONCOGENE (Basingstoke: Nature Publishing Group.) pp. 3349-3365 - issn: 1476-5594 - wos: WOS:001316838400001 (0) - scopus: 2-s2.0-85204520129 (0)

11573/1674490 - 2023 - Combined inhibition of polyamine metabolism and eIF5A hypusination suppresses colorectal cancer growth through a converging effect on MYC translation
Coni, Sonia; Bordone, Rosa; Ivy, Devon Michael; Yurtsever, Zuleyha Nihan; Di Magno, Laura; D'amico, Rodrigo; Cesaro, Bianca; Fatica, Alessandro; Belardinilli, Francesca; Bufalieri, Francesca; Maroder, Marella; De Smaele, Enrico; Di Marcotullio, Lucia; Giannini, Giuseppe; Agostinelli, Enzo; Canettieri, Gianluca - 01a Articolo in rivista
paper: CANCER LETTERS (Elsevier Science Ireland Limited:PO Box 85, Limerick Ireland:011 353 61 709600, 011 353 61 61944, EMAIL: usinfo-f@elsevier.com, INTERNET: http://www.elsevier.com, Fax: 011 353 61 709114) pp. - - issn: 0304-3835 - wos: WOS:000955037000001 (14) - scopus: 2-s2.0-85150380153 (16)

11573/1606202 - 2020 - Cannabinoid CB2 receptors mediate the anxiolytic-like effects of monoacylglycerol lipase inhibition in a rat model of predator-induced fear
Ivy, D.; Palese, F.; Vozella, V.; Fotio, Y.; Yalcin, A.; Ramirez, G.; Mears, D.; Wynn, G.; Piomelli, D. - 01a Articolo in rivista
paper: NEUROPSYCHOPHARMACOLOGY (Elsevier Science Incorporated / NY Journals:Madison Square Station, PO Box 882:New York, NY 10159:(212)633-3730, EMAIL: usinfo-f@elsevier.com, INTERNET: http://www.elsevier.com, Fax: (212)633-3680) pp. 1330-1338 - issn: 0893-133X - wos: WOS:000531762900001 (34) - scopus: 2-s2.0-85085116903 (35)

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