The role of autophagy in oncogenesis and anticancer therapy is contradictory (1-8). Chronic suppression of autophagy may stimulate oncogenesis. However, once a tumor is formed, autophagy inhibition may be a therapeutic goal for radiosensitization and chemosensitization. Multiple oncogenes (in particular phosphatidylinositol 3-kinase, PI3K; activated Akt1; and antiapoptotic proteins from the Bcl-2 family) efficiently suppress autophagy. In adition, several tumor suppressor proteins (such as BH3-only proteins; death-associated protein kinase-1, DAPK1; the phosphatase that antagonizes PI3K, PTEN; tuberous sclerosic complex 1 and 2, TSC1 and TSC2; as well as LKB1/STK11) stimulate autophagy, meaning that their loss reduces autophagy. Beclin-1, which is required for autophagy induction, acts as a haploinsufficient tumor suppressor protein, and other essential autophagy mediators (such as Atg4c, Bif-1 and UVRAG) have been accused to act as oncosuppressors. One of the central tumor suppressor proteins, p53 exerts an ambiguous function in the regulation of autophagy. When present in the nucleus, p53 can act as an autophagy-inducing transcription factor, presumably through the induction of a selected panel of autophagy inducers comprising Dram1, Sestrin1 and Sestrin2. However, within the cytoplasm, p53 exerts a tonic autophagy-inhibitory function, and its degradation is actually required for the induction of autophagy. The knockout or knockdown of p53 induces autophagy, suggesting that the preponderant effect of p53 is autophagy inhibition. We have found that retransfection of p53-deficient carcinoma cells with wild type p53 decreases autophagy down to baseline levels. Surprisingly, one third among a panel of multiple cancer-associated p53 single amino acid mutants also inhibited autophagy when transfected into p53 knock-out cells. Those variants of p53 that preferentially localize to the cytoplasm effectively repressed autophagy, whereas p53 mutants that display a prominently nuclear distribution failed to inhibit autophagy. The investigation of a series of deletion mutants revealed that removal of the DNA-binding domain from p53 fails to interfere with its role in the regulation of autophagy. Altogether, these results identify the cytoplasmic localization of p53 as the most important feature for p53-mediated autophagy inhibition. Moreover, the structural requirements for the two biological activities of extranuclear p53, namely induction of apoptosis and inhibition of autophagy, are manifestly different. References: 1. Kroemer G, Levine B. Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol. 2008 Dec;9(12):1004-10. 2. Tasdemir E, Maiuri MC, Orhon I, Kepp O, Morselli E, Criollo A, Kroemer G. p53 represses autophagy in a cell cycle-dependent fashion. Cell Cycle. 2008 Oct;7(19):3006-11. 3. Mutant p53 protein localized in the cytoplasm inhibits autophagy. Morselli E, Tasdemir E, Maiuri MC, Galluzzi L, Kepp O, Criollo A, Vicencio JM, Soussi T, Kroemer G. Cell Cycle. 2008 Oct;7(19):3056-61. 4. Control of autophagy by oncogenes and tumor suppressor genes. Maiuri MC, Tasdemir E, Criollo A, Morselli E, Vicencio JM, Carnuccio R, Kroemer G. Cell Death Differ. In press 5. The effects of p53 on whole organism longevity are mediated by autophagy. Tavernarakis N, Pasparaki A, Tasdemir E, Maiuri MC, Kroemer G. Autophagy. 2008 Oct 1;4(7):870-3. 6. Levine B, Sinha S, Kroemer G. Bcl-2 family members: dual regulators of apoptosis and autophagy. Autophagy. 2008 Jul 1;4(5):600-6. 7. Tasdemir E, Maiuri MC, Galluzzi L, Vitale I, Djavaheri-Mergny M, D'Amelio M, Criollo A, Morselli E, Zhu C, Harper F, Nannmark U, Samara C, Pinton P, Vicencio JM, Carnuccio R, Moll UM, Madeo F, Paterlini-Brechot P, Rizzuto R, Szabadkai G, Pierron G, Blomgren K, Tavernarakis N, Codogno P, Cecconi F, Kroemer G. Regulation of autophagy by cytoplasmic p53. Nat Cell Biol. 2008 Jun;10(6):676-87. 8. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008 Jan 11;132(1):27-42.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr SY21-2.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009