although the regulatory mechanisms of autophagy are partially known , the exact function of autophagy in cancer is still controversial . when analyzing the intricate relationship between autophagy and cancer , a common challenge is to determine whether autophagy protects cell survival or contributes to cell death . to resolve the role of autophagy in cancer cell fate , several hypotheses have been put forward . one hypothesis proposes that the role of autophagy varies depending on the stage of tumor development . for instance , autophagy limits tumor formation in early stages but favors tumor cell survival , invasion , and metastasis after tumors have formed , . another hypothesis suggests that autophagy can affect tumorigenesis in a cell- or tissue - specific manner , . therefore , at the molecular level , autophagy plays either a pro - survival or a pro - death role by regulating tumor suppressor genes or oncogenes . these autophagic pro - survival or pro - death genes , and the corresponding proteins , can integrate into cancer cell signaling networks and ultimately regulate cell survival or death . autophagy is stimulated by nutrient deprivation , hypoxia , cytokines , hormones , and dna damage . the early stages of activation require atg1 and atg13 , which in turn can be inhibited by mtor . docking and fusion refer to the maturation of autolysosomes and are promoted by rab7 , lamp1 , lamp2 , skd1 , vtil 1b , and the escrt complex . in the last stage , atgs play a key role in the formation of autophagosomes and regulation of autophagic activity ; furthermore , they are closely linked to cancer initiation and progression . silencing some essential atgs , such as atg3 , atg4 , beclin-1/atg6 , atg10 , and atg12 , can sensitize cancer cells to a wide spectrum of stressful conditions . additionally , targeting selected protein kinases involved in autophagy regulation with small molecule kinase inhibitors may be another feasible approach in cancer treatment . a number of protein kinases regulate the induction of autophagy following nutrient deprivation or other cellular stresses . the following protein kinases have been reported to activate protective autophagy in cancer cells as a response to cytotoxic agents , including amp - activated protein kinase ( ampk ) , glycogen synthase kinase 3 ( gsk3 ) beta , extracellular signal - regulated kinases 1 and 2 ( erk1/2 ) , and eukaryotic elongation factor-2 kinase ( eef-2k). mtor , an evolutionarily conserved serine / threonine kinase , serves as the main negative regulator of autophagy in cancer cells . only mammalian target of rapamycin complex 1 ( mtorc1 ) is sensitive to inhibition by rapamycin ; therefore , we focus on the role of mtorc1 in autophagy . three major mtorc1-inducing pathways have been elucidated , including the pi3k - akt pathway and the mapk / erk pathway , consisting of ras - proto - oncogene serine / threonine - protein kinase ( raf-1 ) , mitogen - activated protein kinase 1/2 ( mek1/2 ) , and extracellular signal - regulated kinase 1/2 ( erk1/2 ) . the lkb1-ampk pathway , consisting of liver kinase b1 and ampk , can inhibit mtorc1 . the tsc2/tsc1 complex , which has a tumor suppressor function in various cancers , is a key point upstream of mtorc1 since tsc2/tsc1 can suppress mtorc1 by inactivating the mtorc1-interacting protein , rheb , . upon pi3k activation , akt phosphorylation of tsc2 destabilizes tsc2 and disrupts its interaction with tsc1 to abolish the negative regulatory effect of the tsc2/tsc1 complex on mtorc1 . phosphorylation of tsc2 by ampk can increase the gap activity of tsc2 , stabilize the tsc2/tsc1 complex , and inactivate rheb , resulting in the inactivation of mtorc1 and the initiation of autophagy . in mammals , two homologs of atg1 , namely uncoordinated 51-like kinase 1 ( ulk1 ) and ulk2 , mammalian autophagy - related protein 13 ( matg13 ) , and scaffold protein fip200 have been identified . under nutrient starvation conditions , mtorc1 disrupts the binding of atg13 with ulk and destabilizes ulk , thereby inhibiting the ulk - dependent phosphorylation of fip200 and autophagy induction by phosphorylation of ulk and atg13 . moreover , mtorc1 regulates autophagy by mediating protein translation and cell growth through phosphorylation of 4e - binding protein 1 ( 4e - bp1 ) and p70s6k . phosphorylation of 4e - bp1 leads to its dissociation from eukaryotic translation initiation factor 4e ( eif4e ) and up - regulates cap - dependent translation . phosphorylation of p70s6k by mtorc1 enhances p70s6k activity and allows it to phosphorylate downstream targets . once activated , p70s6k phosphorylates eukaryotic elongation factor 2 kinase ( eef2k ) to relieve elongation factor 2 ( eef2 ) from inhibition by eef2k in addition to promoting autophagy . deptor , an inhibitor of mtorc1 and mt0rc2 , inhibits mtorc1 and mt0rc2 by directly binding to them both . deptor is subjected to proteasome - dependent degradation upon serum stimulation to ensure mtor activation . p53 , a well characterized human tumor suppressor gene involved in genotoxic stress response and dna damage repair , also participates in autophagy regulation . intriguingly , the role of p53 in autophagy seems to be paradoxical depending on its subcellular localization , which may dictate whether p53 contributes to cancer cell survival or death . in the nucleus also , p53 can promote autophagy through targeting multiple genes that code for pro - autophagic modulators , including dapk-1 , damage - regulated autophagy modulator ( dram ) , pro - apoptotic bcl-2 proteins ( e.g. , bad , bax , bnip3 , and puma ) , sestrin1/2 , and tsc2 . notably , sestrin1 and sestrin2 , which are usually expressed under conditions of dna damage and oxidative stresses , are negative regulators of mtorc1 and execute their function through activation of ampk and tsc2 ; thus , sestrin1/2 establish a connection between p53 and autophagy through mtorc1 . the autophagy induced by loss of p53 promotes the survival of p53-deficient cells to sustain high atp levels under conditions of hypoxia and nutrient depletion . therefore , p53 signaling controls autophagy in an ambiguous fashion that depends on its subcellular localization and plays a two - sided role in cancer . beclin-1 , the mammalian homolog of atg6 and a bcl-2 interacting coiled - coil protein , is essential for the formation of double - membrane autophagosomes , which are required in the initial step of autophagy . beclin-1 can promote interaction of bcl-2 with other autophagy regulators , such as vps34 ( pi3k ) , p150 , uvrag , bif1 , atg14l , and rubicon , to form huge protein complexes . additionally , beclin-1 is a haploinsufficient tumor suppressor gene . uvrag , a major positive mediator of beclin-1 , can directly and markedly enhance pi3kiii lipid kinase activity , thus , facilitating autophagy . through mediating the beclin-1/pi3kiii complex , bif-1 , another positive mediator of beclin-1 , can interact with beclin-1 through uvrag to regulate autophagy and suppress tumorigenesis . following dissociation of beclin-1 from bcl-2 , autophagy may be activated depending on whether bcl-2 has been phosphorylated by the starvation - activated c - jun n - terminal kinase ( jnk ) . the tumor suppressor function of beclin-1 is supported by the identification of its mediators in tumorigenesis . bcl-2 inhibits autophagy through interacting with beclin-1 as beclin-1 contains a bh3 domain that facilitates the interaction of beclin-1 with bcl-2 . by interacting with beclin-1 , bcl-2 blocks the interaction of beclin-1 with pi3kiii , decreases pi3kiii activity , and down - regulates autophagy . overall , beclin-1 may enhance autophagy and inhibit tumorigenesis by forming signaling complexes mediated by positive and negative regulators , which suggests a crucial role for beclin-1 in cancer . mounting evidence has demonstrated that mitochondria , the main source of reactive oxygen species ( ros ) in cells , may orchestrate the autophagic process in cancer initiation and progression . for instance , ros play multifaceted roles as a  molecular switch  in the regulation of several core autophagic pathways ( e.g. , atg4-atg8/lc3 , beclin-1 , pten , p53 , pi3k - akt - mtor , and mapk signaling ) that may jointly seal the fate of cancer cells . mapks and p21-activated kinases ( pak ) , two classes of downstream signaling molecules regulated by ros , are thought to be the major signaling pathways for driving cancer cell metastasis , . in summary , all of the aforementioned survival / death signaling pathways involved in atgs , the mtor subnetwork , the beclin-1 interactome , p53 signaling , and ros may play crucial roles in autophagy - related cancer signaling networks . this suggests that autophagic pathways could be promising new targets in cancer drug development , which we will discuss in the following section . evidence suggests that induction of autophagy may help transform tumor phenotypes during cancer therapy . at this time , several novel strategies are being used to target autophagic signaling pathways for drug discovery in cancer treatment because a number of autophagy - inducing drugs have been identified as potential cancer therapeutic agents. several autophagy - inducing agents are already being used to treat different human cancers and should be further explored both at the bench and in the clinic . tumor cells can use autophagy to supply nutrients and energy , and promote tumor survival when nutrients are limited . therefore , some drugs have been developed to block autophagic processes so as to suppress tumor progression . autophagy process can be divided into several phases , including the initiation period , docking and fusion of autophagosomes with lysosomes , and catalytic degradation of cytoplasmic materials inside autolysosomes . pi3k inhibitors , including 3-methylade - nine ( 3-ma ) , wortmannin , and ly294002 , can interfere with or block autolysosome formation and result in the inhibition of autophagy . also , it has been observed that cancer cells undergo increased autophagy and are more sensitive to lysosomotrophic agents . bafilomycin a1 , vinblastine , and nuokaodazuo can inhibit the fusion process to interrupt autophagy . bafilomycin a1 , a type of macrolide antibiotic derived from streptomyces griseus , has been reported to block the fusion of autophagosomes with lysosomes in tumor cells . two anti - malarial drugs , hydroxychloroquine ( hcq ) and chloroquine ( cq ) , can inhibit lysosomal acidification and prevent the degradation of autophagosomes , thereby suppressing autophagy in myc - driven lymphoma and increasing the antitumor effects of cyclophosphamide. in imatinib - resistant bcr - abl - positive chronic myeloid leukemia ( cml ) cell lines , cq enhanced cell death by inhibiting autophagy and strengthened the activity of vorinostat , an histone deacetylase ( hdac ) inhibitor , . in combination with the anti - malarial drug quinacrine , cq remarkably sensitized gastrointestinal stromal tumor cells to imatinib , both in vitro and in vivo , and reinforced the efficiency of quinacrine . cq has recently been reported to be able to inhibit therapy - induced autophagy and to increase cell death in established tumors , leading to tumor regression . nevertheless , autophagy is not only a survival response that opposes growth factor and nutrient deprivation but also an important mechanism for tumor cell suicide . recently , an increasing amount of data have suggested that autophagy , as a mechanism of type ii pcd , may present new opportunities for developing alternative anti - cancer therapies . tamoxifen , an antagonist of estrogen receptor ( er ) , has a high binding affinity for the microsomal antiestrogen binding site ( aebs ) , a hetero - oligomeric complex involved in cholesterol metabolism . tamoxifen and other aebs ligands induce breast cancer cell autophagy through inducing sterol accumulation , . these data indicate a therapeutic implication for selective aebs ligands in breast cancer management and reveal a mechanism that may explain the induction of autophagy in mcf-7 cells by tamoxifen and other selective er modulators , . imatinib ( gleevec ) , an inhibitor of tyrosine kinases , can induce autophagy in multidrug - resistant kaposi 's sarcoma cells , . hdac inhibitors , such as suberoyla - nilide hydroxamic acid ( saha ) , have been reported to be able to induce autophagy and cell death in hela cells independent of caspase - dependent apoptosis ; thus , initiation of autophagic cell death by saha has clear therapeutic implications for apoptosis - defective tumors . it is well known that mtor is a major regulator of cell growth that has also been implicated in tumorigenesis , . the tumor suppressing action of rapamycin , an inhibitor of mtor , is linked to induction of autophagic cell death . in addition to these agents , there are also other interesting examples of autophagy - inducing agents from traditional chinese medicine . one such traditional chinese compound , arsenic trioxide ( as2o3 ) , has been reported to be able to induce apoptosis through cytochrome c release and caspase activatiori , . interestingly , recent studies showed that treatment of human t - lymphocytic leukemia cells with as2o3 led to cytotoxicity through inducing autophagy . a bcl-2 family member , bcl-2-adenovirus e1b 19-kda - interacting protein 3 ( bnip3 ) , was reported to play a pivotal role in as2o3-induced autophagic cell death in malignant glioma cells , . additionally , polygonatum cyrtonema lectin ( pcl ) was shown to be able to induce autophagic cell death via a mitochondria - mediated ros - p38-p53 pathway in human melanoma a375 cells , . based on the aforementioned examples , autophagy may play an important role in the cytotoxic effects of these compounds that could spark new autophagy - targeted cancer therapeutic strategies , . additionally , dna damage agents have been found to be able to induce autophagy in tumor cells . for example , temozolomide ( tmz ) , an alkylating agent , is widely used to treat primary and recurrent high - grade gliomas . the cytotoxicity of tmz is thought to result from the formation of o-6-methylguanine in dna , which mispairs with thymine during dna replication and triggers futile cycles of the mismatch repair system and subsequent dna damage . it was shown that tmz induces autophagy and that pharmacologic inhibition of autophagy could influence cellular outcome . much work is needed to determine how modulators of autophagy impact cancer initiation , progression , and therapeutic response , and to determine exactly why targeting autophagic signaling pathways may be a valuable strategy for cancer drug development . autophagy plays a dual role in the regulation of pro - survival and pro - death signaling pathways in a variety of diseases , including cancer . several key autophagic mediators , including atgs , pi3k , mtor , p53 , beclin-1 interacome , and ros , have been demonstrated to play pivotal roles in the complex autophagic network in cancer cells . however , much work is needed to determine the intricate molecular mechanisms of autophagy in cancer , to define how crucial modulators of autophagy in cancer impacts cancer initiation and progression , and to elucidate why targeting autophagic signaling pathways is promising for cancer therapeutics . furthermore , recent biological insights can provide a fertile foundation for launching this next round of small - molecule drug discovery . these discoveries are being driven by an abundance of structural information on the potential targets ; therefore , x - ray crystallography , nuclear magnetic resonance ( nmr ) , and structural bioinformatics - docking techniques will be invaluable in the efforts to target autophagic pathways for drug discovery . more importantly , there is an increasing emergence of sophisticated mathematical models , such as the naive bayesian framework and support vector machine ( svm ) , for the disruption of protein - protein interactions ( ppis ) . the best hope for targeting autophagy as a therapeutic intervention may lie in the discovery of agents that are able to target the altered autophagy - regulating signaling pathways , or even the autophagic network , rather than targeting the individual genes or proteins . a better understanding of the autophagic ppi network will provide useful insights into how these hub proteins and autophagy - related signaling pathways can be exploited as potential therapeutic targets for treatment of human diseases ( figure 2 ) . due to the complex , two - sided nature of autophagy , establishing the dual role of autophagy in tumor survival vs. death may assist in determining therapeutic potential . inhibiting autophagy may enhance the efficacy of currently used anti - cancer drugs and radiotherapy . in addition , promoting autophagy may induce cancer cell death with a high threshold to apoptosis . therefore , both strategies have significant potential to be translated into ongoing clinical trials that may provide more valuable information regarding whether targeting autophagic pathways in tumor cells would be a promising avenue for cancer therapeutics . in addition , with increasing accuracy , small molecules that inhibit or promote protein - protein interactions ( ppis ) can be screened as potential candidate drugs . thus , the autophagic ppi network can provide more novel insights into how these hub proteins and their autophagic pathways can play key roles as potential drug targets in cancer treatment .