**13. Autophagy and cancer**

Regarding the role played by autophagy in cancer, mounting evidences suggest that autophagic cell death functions as a tumour suppressor mechanism. Several tumour suppressor proteins have been shown to induce autophagy. Supporting this idea, there are also several works showing that certain oncogenic proteins inhibit autophagy. Most of this oncogene products form part of the classic PI3K-Akt-mTOR pathway. In the following section, we summarize the literature on the role played by key tumour suppressors and oncogene products in the regulation of autophagy and the involvement of autophagic genes in cancer.

Cell Death and Cancer, Novel Therapeutic Strategies 89

the monoallelic deletion or mutation of UVRAG has been observed in several human

*Bif-1* is also a tumour suppressor that promotes autophagy. Similar to UVRAG, Bif-1 is a positive regulator of Beclin 1, as it enhances its interaction with PI3KC3, thus increasing autophagy. Consistently, it has been shown that loss of Bif-1 prevented the formation of autophagosomes and induced the development of spontaneous tumours in mice [144]. Furthermore, expression of Bif-1 is significantly reduced in prostate, colon, urinary bladder and gastric tumours [146,148,149]. The precise mechanism of Bif-1 in suppressing tumourigenesis has not been fully clarified, but it is reasonable to presume that its tumour inhibitory activity is associated with its role in inducing autophagy. Some groups have also suggested that Bif-1 suppresses tumour growth through its interaction with proapoptotic

Most of the oncogenic genes that regulate autophagy described to date are key proteins of the PI3K-Akt-mTOR pathway. These proteins inhibit autophagy and promote

*mTOR:* the best-studied downstream substrate of Akt is the serine/threonine kinase mammalian target of rapamycin (mTOR). In mammals, mTOR exists in two different complexes, known as mTORC1 and mTORC2. In the mTORC1 complex, mTOR is bound to a protein called Raptor, and in the mTORC2 complex, mTOR is bound to Rictor. mTORC1 is best known for its role in regulating protein synthesis through two of its substrates, 4E-BP1 and p70S6K [151]. Akt can directly phosphorylate and activate mTOR, or activate it indirectly by phosphorylation and inactivation of TSC2. When TSC2 is inactivated by phosphorylation, it can no longer associate with TSC1, thus abolishing the inhibitory effect of TSC1-TSC2 complex on mTORC1. As a result, mTOR is activated and signals to its downstream targets p70S6 kinase, ribosomal protein S6 and 4EBP-1/eIF-4E to control protein translation and proliferation [152]. mTORC1 is not only a key regulator of proliferation and survival, but also a master inhibitor of autophagy. Under nutrient-rich conditions, mTORC1 is activated and phosphorylates ULK1, ULK2 and mAtg13, inhibiting the initiation of autophagy. In contrast, in nutrient starvation conditions mTORC1 is inactivated and dissociates, resulting in activation of ULK1 and ULK2, which initiates the autophagy cascade [151]. The PI3K-Akt-mTOR pathway is probably the most commonly activated signalling pathway in human cancers [124]. This route is activated aberrantly in many types of tumours, and hence, inhibited autophagy and increased proliferation and protein synthesis are often observed. For example, many human cancers are characterized by activating mutations in specific components of the signalling pathway that connect Receptor tyrosine kinases to mTOR, including Ras, PI3K and Akt. Somatic mutations in PIK3CA gene encoding the catalytic subunit of class I PI3K frequently occur in cancers of colon, breast, brain and lung [153]. PTEN, another regulator of PI3KI-Akt pathway, is a tumour

cancers such as colon, gastric and breast cancer [145-147].

**13.2. Oncogenic genes that regulate autophagy** 

suppressor that is found to be mutated in many types of cancer.

Bax [150].

carcinogenesis.
