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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 5  |  Issue : 3  |  Page : 260-266

Contrasting role of autophagy in different types of cancer: A review toward biomarkers and therapeutic improvement


University of Calcutta, Kolkata, West Bengal, India

Date of Submission21-Jun-2021
Date of Acceptance10-Aug-2021
Date of Web Publication7-Sep-2021

Correspondence Address:
Pallab Chakraborty
University of Calcutta, Kolkata, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_123_21

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  Abstract 


Autophagy, the major cellular pathway, is known not only for the degradation and recovering in mammalian cells but also it maintains the cellular energy homeostasis and produces the building blocks. However, if the process starts destroying the essential ones other than the bad proteins, then the normal cellular control will be lost, and here, we see similar kinds of phenomena in cancer. It has been reported by previous papers related to this field that the novel pathway has paradoxical role in cancer, as it acts as both tumor promoter and suppressor. Therefore, autophagy could provide new resources for the improvement of antitumor drugs in near future. Here, in this review, we will know about the autophagy process in brief. We will also try to understand the contrasting role of autophagy in different cancers types, its significance as prognostic markers and its therapeutic implication for cancer treatment in the near future.

Keywords: Autophagy, biomarkers, cancer, paradoxical role, therapeutic strategy


How to cite this article:
Chakraborty P. Contrasting role of autophagy in different types of cancer: A review toward biomarkers and therapeutic improvement. Biomed Biotechnol Res J 2021;5:260-6

How to cite this URL:
Chakraborty P. Contrasting role of autophagy in different types of cancer: A review toward biomarkers and therapeutic improvement. Biomed Biotechnol Res J [serial online] 2021 [cited 2021 Dec 1];5:260-6. Available from: https://www.bmbtrj.org/text.asp?2021/5/3/260/325606




  Introduction Top


The process that is related with cellular and tissue homeostasis and the degradation and recycling process of cytosolic compound[1],[2] known as autophagy has been found to be connected with cancer.[3],[4] After several researches, it is now disclosed that this catabolic process (autophagy) has both tumor-suppressive and tumor-promoting activities.[5],[6] The cytoprotective role of this process such as, cellular survival during stressed condition, under low nutrients and oxygen, is helpful for cancer growth. In pancreatic cancer, the autophagy related genes (Atgs) are found increased, means it utilizes the autophagy process for its own survival (cytopotective role of autophagy).[7],[8] On the other hand, it reduces reactive oxygen species (ROS) level, activates autophagy-related cell death in cancer,[6],[9] and tries to control the disease progression like as a tumor suppressor. Its performed paradoxical role in cancer.[10] In this regards some clinical anticancer drugs are used to activate autophagy process and kill cancer, but some of the study found that it may also suppress the antitumor immune response, and thus in such cases inhibition rather activation of autophagy could improve the immune activity against cancer.[5],[6] The major actions of this process vary in different cancer types, and thus, this field is still now an active area of research. If we can create a great idea about how this process regulates differently in different types of cancer, it will be helpful to tackle the disease very effectively in the near future. Here, in this review, I have discussed the current knowledge about the autophagy, its major role in different type's cancer, how biomarkers concepts related and its therapeutic implication for better treatments.


  Brief Discussion about Autophagy Top


The 2016 Noble Prize for Physiology or Medicine was awarded to Dr. Yoshinori Ohsumi, for outstanding work on the mechanisms of autophagy. Autophagy which is the highly conserved self-eating process enables the transport of cytoplasmic contents to lysosome for recycling, degradation procedure, and productions of new building blocks like nucleic acid.[1]

Instead of cellular homeostasis process, it has very important role in cellular development and differentiations, and thus, defects on this major process lead to several neuronal disorders, metabolic disease as well as cancer.[6],[7] According to how the cellular materials are delivered to lysosome,[1] the autophagy process is divided into three major types – macroautophagy, microautophagy, and chaperon-mediated autophagy (CMA). In macroautophagy, the double-membrane vesicle called autophagosome fused with the cytoplasmic content and then merges with lysosome and formed autophagolysosome and recycled by the hydrolytic enzymes.[8] In microautophagy, directly the cytoplasmic contents are engulfed by the lysosome without any intermediate vesicle,[9] and in case of CMA, the damaged proteins or cytoplasmic materials bearing KFERQ like specific amino acids are recognized by heat-shock proteins 70 and transported to lysosome through the lysosomal associated membrane protein 2A receptor.[11],[12] In the complete process of autophagy, so many genes are involved such as ULK1/2, ATG2A/B, ATG5, ATG3, ATG4A-D, ATG14 L, and Beclin-1 and play a crucial role reviewed by Li et al., 2020.[13] A small interaction performed by me with STRING between the genes also represented in [Figure 1] that found the proteins have more interactions among themselves than what would be expected for a random set of proteins of similar size, drawn from the genome.
Figure 1: Interaction between autophagy-related gene and genes from STRING (the number of nodes: 23, number of edges: 246, average node degree: 21.4, average local clustering coefficient: 0.976, and Protein protein interaction (PPI) enrichment P value: <1.0e-16. This means that the proteins have more interactions among themselves than what would be expected for a random set of proteins of similar size, drawn from the genome. The data directly written here as shown during the study by software)

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In presence and absence of various stimuli like stress, nutrients, the autophagy process gets regulated. The Mammalian target of rapamycin (mTOR) detects the chemical signals and in the presence of signals the mTORC1 which is a subtype of mTOR, inhibits the autophagy by preventing activation of Unc-51-like autophagy-activating kinase-1 (ULK1) and Unc-51-like autophagy-activating kinase-2 (ULK2).

On the other, the initiation of autophagy performed by the AMP activated protein kinase (AMPK) which directly activate ULK1 by phosphorylation. So basically when the ULK 1 gets activated, the Atg proteins are organized onto the preautophagosomal structure (PAS), the main site for the autophagosome formation.[13] Then, the other functional units such as PI3K complex, ATG9A system, ATG12-conjugation system, and light chain 3 (LC3)-conjugation system are targeted to the PAS for the formation of autophagosome.[16],[17] Then, gradually the rest of the process takes place as mentioned in [Figure 2]. The macroautophagy is divided into two types: one is conventional and another is alternative.[18] In general after initiation of the autophagy process, the membrane formed by the involvement of the autophagy-related genes (Atg) & the microtubule-associated protein 1 light chain 3 (LC3) [15]. Then gradually the membrane elongates and produces autophagosome which finally get fused with lysosome to complete the degradation process. For conventional autophagy needs Atg5 and Atg7, and this is related with LC3 alteration but in alternative autophagy occurs autonomously of Atg5 and Atg7, please see [Figure 2] for a brief description about these.[18] Here, after the macroautophagy, will be discussed as autophagy in cancer hallmarks and mainly its contrasting role for different types of cancer.
Figure 2: Simplified schematic of autophagy process

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  Autophagy and Different Types of Cancer Top


As earlier said, the autophagy can be function as neutral, tumor promoter, and tumor suppressor. Evidence suggest that in cancer, autophagy regulates cancer hallmarks, such as tumor progression, metastasis, angiogenesis, tumor microenvironment, cell damage prevention.[10],[13],[15] The chronic inflammation that is major future markers for cancer development is regulated by autophagy itself.[13] Any modification of this process can lead to varying the tumor microenvironment, cause inflammations, uplift oxidative stress, and create cancer-causing mutations.[19],[20] It is also reported that autophagy helps to remove the damaged protein organelles and ROS, maintaining genome stability, metabolism and mitochondrial functions, inhibiting DNA damage, all this supports that it protects cancer cells from cell damage[21] and it promotes to the aggressive nature of the cancers by helping in metastasis.[13],[22] In advanced stage of metastasis, this process helps to the new metastatic cells by inducing dormancy that survives themselves to a new unknown environment[23] and found upregulated in metastatic cancer for the sustainment of secondary tumor.[13] Autophagy has emerging functions in secretion of angiogenesis-related factors,[24] and how the autophagy modulates still understudied. The different profiles of autophagy in different types of cancer are individually discussed below.

Cervical cancer

Cervical cancer, the highest morbidity and highest mortality for woman worldwide, is mainly caused by human papillomavirus (HPV).[25] At present, it is now observed that for the disease progression and development, autophagy executed a key role.[26] Previous research reported that the autophagic gene Beclin-1 when over expressed it inhibits the proliferation and growth of HeLa cells both invitro, and invivo[27] and the proliferation of CaSki human cervical cancer.[28] But normally it is down regulated in cancer thus supports tumor genesis and cervical cancer development.[25] The autophagy also is found to prevent the cisplatin-induced apoptosis in HeLa cells.[29] An antiautophagy factors named ATAD3A highly expressed in cervical cancer that is correlated with HPV infection[30] and helps in escaping cell death and autophagy.[26] Some of the plant-derived drugs such as paclitaxel and resveratrol, show to induce autophagy and trigger cell death in cancer.[26] Therefore, targeting autophagy, mainly induction may, helps in therapeutics improvement for cervical cancer treatment and will help to identify clinically relevant biomarkers in cervical cancer in the near future. More detailed findings and studies are warranted to know every single involvement of autophagy-related proteins with this cancer type so that inhibitors can be used for them to treat this cancer.

Breast cancer

Breast cancer is a very common and aggressive type of cancer that covers majority of the women.[31] Evidence suggest that here also autophagy performed a very crucial role in disease development and progression.[31],[32],[33] Autophagy-related major proteins such as Beclin-1 and LC3-II/I protein conversion levels are much higher in cancer-associated fibroblasts (CAFs) vital in malignant cancer progression than normal fibroblast and this CAF autophagy may boost triple-negative breast cancer (TNBC) cell proliferation.[31],[34] Inhibition of autophagy in TNBC cell lines in vitro increases radiosensitivity, thus inhibition of autophagy helpful for TNBC treatment.[34],[35] Sometimes, excessive autophagy can also trigger cell death like RL71-triggered excessive autophagic cell death in TNBC.[33] In case of her-2 + breast cancer, researchers recognized that Beclin-1 autophagy-related protein deficiency increases the HER2-targeted therapy, so inhibition of autophagy[31] as a combination with others anticancer drugs will be a great approach to treat this. In case of apoptosis, autophagy has a huge association. The Bcl-2 that is antiapoptotic factor is also a negative regulator of autophagy-related protein Beclin-1; the Beclin-1 and ATG5 on the other are also found to prevent cell death process by degrading the active caspase-8.[31],[36] The association of autophagy and metastasis also identified. The Snail and Slug, crucial controllers of Epithelial-to-mesenchymal transition (EMT), endorse EMT by inducing the loss of epithelial (E)-cadherin-mediated adhesion. They are associated with autophagy and it was reported that deficiency of autophagy promotes EMT by stabilizing Twist1.[31] The LC3B has been shown to be linked with lymph node metastasis and decreased survival in human breast cancer.[37] Recent data support that, the downregulation of ATG5-dependent macroautophagy by chaperone-mediated autophagy can uphold breast cancer cell metastasis.[38] Role of local immune cells, cancer microenvironment, and its impacts on disease progression along with autophagy modification need to be decoded and it is very important to find how the autophagy shifted for cancer survival.

Colorectal cancer

The association between the colorectal cancer (CRC) and autophagy also recently observed.[39] In vivo evidence suggest that autophagy has a key role in CRC development as it is reported that in early stage, autophagy being active in CRC formation.[40] Various CRC cell lines respond differently on autophagic inhibition.[41] In the classical ApcMin/+ mouse model, it was found that inhibition of autophagy helps to increase CD8 immune response and reduce tumor growth.[40] Recent research also supports that inhibition of autophagy in vitro does not contribute to CRC cell proliferation but in contrast in vivo Caco-2/15 and HCT116 cells being sensitive to autophagy inhibition whereas SW480 and LoVo cells displayed increased tumor growth.[41] HCT116 and Caco-2/15 cells were found to substantially increase their autophagic flux upon nutrient stress, compared to other CRC cells.[41] As several studies already reported that sometimes, inhibition of autophagy causes hyperproliferation,[42] the same thing observed in SW480 was caused by ectopic activation of the AKT and mTOR pathways.[41] These findings focus autophagy inhibition can lead in specific cellular contexts to compensatory mechanisms upholding tumor growth. On the other, the frame shift mutations with mononucleotide repeats have been found in ATG2B, ATG5, ATG9B, and ATG12 genes in CRC, which may be involved in cancer development by disregulating the autophagy.[43] The essential autophagy gene Beclin-1 was upregulated in CRC, suggesting again for this that the enhancement of autophagy can promote tumor genesis and overexpression of the Beclin-1 plays a crucial role in tumor formation.[44] By applying histone deacetylase inhibitors, γ-irradiation that is mainly cancer therapy used in colon cancer[45] and others too which can induce autophagy in turn functions as a cytoprotective to prevent cancer cell death upon treatment add to cancer recurrence and metastasis and prevent cancer therapy and tumor cell killing.[13] For better treatment, it is necessary to find the best therapeutic approach with autophagy by doing more research in these fields in the future.

Ovarian cancer

It is fifth leading cause of cancer related death among women's.[46] The difficulty to diagnose at early stage and the tenacity of dormant drug-resistant cancer cells that cause relapse are the main reasons for the high death rate in ovarian cancer patients.[47] The oncogenes or oncogene-suppressors the genes are mainly phosphatase and tensin (PTEN), aplasia ras homolog member I (ARHI), and p53, and LC3, Beclin-1, and DRAM autophagic process-related genes are found altered that have direct or indirect association with autophagy may have potential impact on radio-and chemotherapeutic treatments and in dormancy in ovarian cancer.[48] The autophagy protein LC3 was found less expressed in highly metastasis ovarian cancer that supports in this cancer, that the LC3-labeled autophagosome not accumulated.[49] Mutation in p53 also has a dominant-negative impact on Bcl-2 genes that inhibit autophagy process in ovarian cancer by interacting with Beclin-1 gene.[47],[50] Recently, it is reported that ARH1 (ARH1; also known as DIRAS3) tumor suppressor gene has a potent role to induce autophagy-dependent dormancy in ovarian cancer.[23] The expression of Beclin-1 has been found downregulated in ovarian cancers, and hyper-expression of Beclin-1 in ovarian cancers is related with a noble chemotherapeutic response.[47] In epigenetic control of autophagy, the miRNAs pattern in ovarian cancer cells, such as miR-30a (negatively regulate Beclin-1), miR-101 (represses the expression of the Atg4) found downregulated in ovarian cancer.[51],[52] Therefore, the concluding point will be activation of autophagy leads to a more aggressive progression of ovarian cancer.

Lung cancer

Lung cancer is one of the most widespread types of cancer that causes death worldwide due to mainly resistance to chemotherapy and radiation therapy like ovarian cancer.[53] It has been reported that majorly modification in apoptosis mechanism that may one of the leading causes for abnormal proliferation along with inattentiveness to cytotoxic drugs[53] used as therapy. Autophagy-related cell death can be used here for treatment. Lung cancer can be subdivided into two types – non-small cell lung cancer (NSCLC) constitutes 85% of all lung cancers now covered in this section hereafter and small-cell lung cancer (rest 15%) according to histological classification.[54] In NSCLC due to several gene mutations autophagy gets modulated, and those mutated genes and their products can be used as biomarkers for NSCLC.[55],[56] Other genes, such as epidermal growth factor receptor, KRAS, LKB1, and PTEN, are closely associated with the mTOR regulation network that is also indirectly maintain autophagy process.[54] Autophagy found inactivated in lung cancer as the negative marker for autophagy or autophagy degradation “p62” has been detected high concentration[57] that p62 accumulation correlates with cancer progression. A recent research proved that a combination therapeutic approach with rapamycin, like The Bcl-2 inhibitor ABT-737, for example, promotes apoptosis and autophagy and can improve the radiation therapy in both in vitro and xenograft lung cancer models.[58] The AZD8055, PI3K inhibitor speed up autophagosome formation and autophagy activation and found to show growth inhibition and tumor regression in NSCLC xenograft models.[54] All these experiments support that in case of lung cancer, the autophagy process found to be suppressed, that's why several drugs are being used to induce autophagy and autophagy-mediated cell death in lung cancer. However, important to note that the induction of autophagy may neither be pro nor antiapoptotic, as flavonoid extracted from Chinese medicinal herb induces endoplasmic reticulum stress-mediated apoptosis and autophagy; however, the autophagic effect neither promotes nor inhibits apoptosis in NSCLC cells.[59]

Prostate cancer

Here also, autophagy found modulated and promote tumorigenesis; thus, several drugs such as inhibitors of autophagy including 3 methyladenine, and siRNAs targeting specific Atgs are used.[60] The serum- and glucocorticoid-induced protein kinase 1 (SGK1) with elevated expression[61] observed in this cancer also particularly the SGK1-overexpressing PCa xenografts displayed accelerated castrate-resistant tumor initiation and in HEK293 cells, SGK1 mutation improved cell migration ability.[62] In a recent study, it is reported that inhibition of the SGK1 gene results reduction of EMT and metastasis both in vitro and in vivo, where it partially induces the autophagy process that down regulates snail and shows antimetastatic effects.[63] Moreover, dual inhibition of mTOR and SGK1 leads to antimetastatic effects on PCa cells.[63] More research is needed to find these types of genes which are can be used to target.


  Discussion Top


Now, after considering all, we make some valuable points toward the therapeutic improvement of cancer.


  Biomarkers Top


As we can see here, that the most of the genes like p62, LC3, Beclin-1 are directly or indirectly associated with the autophagy process and cancer progression, so they can be used as novel biomarkers for the detection of individual cancer types depending upon their expression profile. Biomarkers assay for those genes and proteins which are expressed in different types of cancer and modulate autophagy process can be used for better diagnosis and prognosis. Biomarker assay for specific genes and proteins those are expressed in different types of cancer associated with autophagy process for better diagnosis and prognosis. These genes also can be used as therapeutic target in cancer treatment.


  Therapeutics Top


For the treatment purpose, there are so many therapeutic strategies that are used in cancer. As you can see in this manuscript that autophagic profile is not the same for all types of cancer, even not in case for subtypes (e.g. breast cancer) and autophagy shows variation that's related with cancer pathogenesis.

Inhibition of autophagy by using drugs or silencing of different Atgs involved in disease progression[19],[26],[29],[35] when it function as cytoprotective will be best for treatment. Sometimes induction of autophagy or overexpression of autophagy related genes (when it acts as cytotoxic) by using chemicals or natural compounds could be meaningful for treatment of cancer. But it is depends upon the autophagic profiles found in different types of cancer.

Moreover, for different types of cancer, different autophagy proteins are found malfunctioned due to cancer microenvironment when some anticancer drugs are being used and causing cancer promotion. Because the proteins involved in this process that creating an obstruction for anticancer drugs as discussed in cancer types, so targeting specific proteins, can maintain autophagy process, normalized its function and can increase therapeutic treatments. Combination approach like using both anticancer drugs and autophagy inhibitor or inducer depends upon types of cancer, may be helpful to enhance its function and improve patient's condition.

The inflammatory cells like neutrophils are found high in cancer and they can generates tissue damaged and further tumor genesis by producing ROX, RNX, protease. As they undergo cell death via autophagy [2],[3],[9],[19], [64], so in this case also induction of autophagy from cancer cell line may increase the life span of the Patient.


  Conclusion Top


It is now clear that autophagy performed both tumor-promoting and tumor-suppressing role and in the future thus it is warranted to focus on the process of autophagy, its proteins how this gets modulated in different types of cancer and how all these findings used for the betterment of cancer treatment. Some limitations are:

  • What are the genetic and epigenetic factors related with autophagy and cancer modulation?
  • [Figure 1] supports that the genes have higher interaction among them so what happened in each cancer, how do they interact? Does there interaction gets changed and as a results lead to cancer promotion?
  • How much the Atgs and proteins are crosstalk with apoptosis-related genes and proteins and acts differently in different types of cancer?
  • What proteins can be used for better prognosis of different types of cancer?
  • In combination therapy which therapy responded most effectively?
  • How to identify in initial stage that which functional stage of autophagy activated (cytoprotective or cytotoxic or neutral) in different types of cancer?


Declaration

The author declares that this work is original and totally done by him. Use or modification of other's articles (open access) data related in this field done after giving appropriate credit to the original author(s) and the source. The author, furthermore, makes no representations that the data available in the referenced papers are free from error.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Abbreviations

Reactive oxygen species (ROS), Chaperon mediated autophagy (CMA), heat-shock proteins (HSP), Lysosomal associated membrane protein 2a (lamp2a), Mammalian target of rapamycin (mtor), Unc-51-like autophagy-activating kinase-1 (ULK1) , Unc-51-like autophagy-activating kinase-2 (ULK2), Amp activated protein kinase (AMPK), Autophagy-related genes (ATG), The microtubule-associated protein 1 light chain 3 (LC3), Pre-autophagosomal structure(PAS), Tumor micro environment (TME), Cancer associated fibroblasts (CAFs), Triple-negative breast cancer (TNBC), Aplasia Ras homologue member I(ARHI), Non-small-cell lung cancer (NSCLC), Small-cell lung cancer (SCLC), Serum- and glucocorticoid-induced protein kinase 1 (SGK1), Damage-regulated autophagy modulator (DRAM), PI3K-Akt signaling pathway (AKT), Kirsten rat sarcoma viral oncogene homolog(KRAS), liver kinase B1 (LKB1).



 
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Autophagy and Di...
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