Autophagy, a self-degradative intracellular process, is an essential mechanism of the cell that facilitates renewal or removal of cellular molecules, thereby balancing the cell’s energy consumption and maintaining homeostasis (Rahman and Rhim, 2017; Rahman et al., 2020a). However, autophagy deregulation is now considered to be one of the most characteristic features for tumor progression (White, 2015). It has recently been revealed that autophagy suppression and a combination of chemotherapeutic treatment have been approached as a potential treatment for cancer (Perez-Hernandez et al., 2019), although this depends on the context and type of cancer. To date, numerous tumor suppressor oncogenes and proteins have emerged as eminent autophagy regulators whose mutation or depletion regulates autophagy as well as tumorigenesis. Evidences have been suggested that p53 which belonging to the tumor suppressor genes may act as an inhibitor or activator of autophagy depending on their mode of action and subcellular localization (Lacroix et al., 2020). Morevoer, physiological role of autophagy in cancer offers a highest possible target for future cancer therapy and is, hence, presently intensively investigated. Therefore, understanding p53 regulation and its role in individual cellular contexts with a suitable approach of autophagy-mediated regulation in cancer is crucial for drugs development that might be targeted autophagy in a specific diseases model.

Tumor suppressor p53 has been implicated in a wide variety of cellular processes, including genomic stability, cell-cycle arrest, DNA repair, apoptosis, cellular senescence, and autophagy (Aubrey et al., 2018; Mrakovcic and Frohlich, 2018). Generally, p53 binds to DNA in the nucleus which regulates transcription of target genes to activate apoptosis (Tang et al., 2021b). Nevertheless, human p53 mutation has been encouraged tumor progression, chemoresistance, and apoptosis (Alvarado-Ortiz et al., 2021). Additionally, p53 inactivation is effectively used as a therapeutic target of a promising approach to trigger anti-cancer therapy (Zawacka-Pankau and Selivanova, 2015). Thus, p53 has a dual role as a positive or negative regulator of autophagy in cancer (Liu and Gu, 2021). Under normal cellular conditions, p53 has been recognized as an autophagy inhibitor, while in response to stress or starvation, p53 might be translocated into the nucleus which endorsed autophagy via transactivation with its target genes (Mrakovcic and Frohlich, 2018; Fang et al., 2021). p53 functions have been modulated via several post-translational modifications as well as different interacting proteins (Soussi, 2000). Among them, 14-3-3 family proteins play an important function in p53 regulation in response to DNA damage (Falcicchio et al., 2020). However, reasons for this difference in wild-type and mutant p53 activities have been triggered apoptosis and cell cycle arrest remain unclear (Parrales and Iwakuma, 2015). Particularly, experimental studies have been confirmed that mutant with gain-of-function variant of p53 in tumors cells are characterized via a higher genomic instability in response to reduce chemotherapeutic which has usually poor prognosis for patients (Liu et al., 2012). In this review, the molecular mechanisms and regulation of autophagy in cancer would be discussed regarding modulation of p53. Additionally, recent progress of autophagy signaling in tumor microenvironment in addition to its targeting for possible cancer therapeutics developments from the pre-clinical trials anong with the challenges in developing autophagy-based cancer therapy (Mukhopadhyay et al., 2021). Therefore, current approaches triggering p53-mediated autophagy regulation in cancer treatment are highlighted and summarized in cancer cells to conventional treatments which are able to overcome chemoresistance in cancer.

Literature-based online databases, Google Scholar, Web of Science, PubMed, Google, and Scopus were accessed to collect information on the published articles that reported molecular mechanism of p53 and autophagy modulation in cancer prevention. Several keywords were used in the search, such as p53, autophagy, cancer, phytochemicals, natural compounds, solid tumors, and lymphomas perspectives role of p53 and autophagy in cancer therapy. Figures were created with the Adobe Illustrator software.

The p53 is a central transcription factor that has the capacity to induce diverse cellular responses likely DNA damage repair, cell cycle arrest, apoptosis, and senescence followed by various stress signals (Figure 1) (Subburayan et al., 2018; Mijit et al., 2020). The master biological function of p53 is to ensure the safety of the DNA uprightness of the cell (Munroe et al., 2020). Along with this, p53 protein operates some additional acts in cellular aging, cell differentiation, and development (Jain and Barton, 2018). The p53 antitumor function is broadly governed by dual approaches; it can promote repair of the DNA damage or promote apoptosis or autophagy to completely remove the irreplaceable damaged materials or cells (Crighton et al., 2006; Janicke et al., 2008). In fact, p53 is a transcription factor of the nucleus which governs the diverse array of cellular processes and escorts transcription of a broad group of target genes of it. At the initial phase of DNA damage, p53 activates and induce cell-cycle arrest of G1-phage which is attributed to repair the DNA damage by promoting the transcription of p21WAF1, GADD45, and p53R2 (He et al., 2020). Following the DNA repair, cells can start come back into the regular cell cycle procedure resulting in p53 itself regulate nuclear integrity to prohibit tumor induction or occurrence (Williams and Schumacher, 2016; Cafaro et al., 2020). On the other hand, p53 is able to apply its pro-apoptotic activities through the removal of the damaged cells (Ingaramo et al., 2018). In this cellular process, p53 is responsible for the transactivation of a wide range of pro-apoptotic target genes that encodes Bax, Bak, Puma, and Noxa proteins belong to BH-3 only protein and playing a role to promote apoptosis in a cell (Moll et al., 2006; Labi et al., 2008) (Figure 1). In this manner, p53 can protect from tumorigenesis or cancer initiation by regulating this complex process.

Autophagy has been categorized as an intracellular self-degradation mechanism through dysfunctional cytoplasmic organelles and aggregated misfolded proteins are terminated via fusion with lysosomes and double-membrane autophagosomes to maintain cellular homeostasis (Krishnan et al., 2020; Miller and Thorburn, 2021). Usually, autophagy process, mainly macroautophagy, has been initiated via the isolation of pre-autophagosome structures called phagophore assembly sites (PAS) (Hurley and Young, 2017). PI3K related to the endoplasmic reticulum (ER) have a vital role to initiate PAS formation (Kotani et al., 2018). Unc-51 like autophagy activating kinase-1 (ULK1), mammalian target of rapamycin (mTOR), and AMP-activated protein kinase (AMPK) facilitate phagophore formation during induction of autophagy (Alers et al., 2012; Rahman et al., 2021a). Nevertheless, VPS34/UVRAG/Beclin-1/AMBRA1 helps in the phagophore formation (Velazquez and Jackson, 2018), followed by membrane elongation and autophagosome formation (Rubinsztein et al., 2012). Lysosome binds to mature autophagosome by the association of ESCRT/SNARE/Rab7 protein complex, resulting in the formation of autolysosomes (Kardideh et al., 2019; Rahman et al., 2021c). Finally, autolysosomes that contain misfolded/aggregated proteins have been degraded via acid hydrolases and provide recycling metabolites and nutrients for maintaining intracellular homeostasis (Figure 2). It has been found that cancer cell fate regulations and development depended on the autophagy process (Wei and Huang, 2019).

Additionally, well-known cellular autophagy mechanism contributing to carcinogenesis is chaperone-mediated autophagy (CMA) which signify lysosomal-mediated degradation process to facilitate cell survival (Chava et al., 2017). It has been found that during serum starvation, CMA and macroautophagy are triggered consecutively signifying that these two paths are not entirely independent while deficiency or blockage one of this pathway may lead to activate other (Kaushik et al., 2008; Cuervo and Wong, 2014). However, CMA has been found to degrade mutant p53 in a lysosome-dependent fashion in cancer cells under nonproliferating conditions (Vakifahmetoglu-Norberg et al., 2016). Later, chaperone-assisted selective autophagy (CASA) was found in skeletal muscle cells which coordinates protein synthesis and degradation and act as an important physiological stimulus crucial for cellular development, respiratory, maintain urogenital systems, and homeostasis of locomotory (Ulbricht et al., 2013). Moreover, CASA machinery ensures proteostasis in addition to regulate essential cellular developments such as proliferation, migration, and adhesion which comprises the molecular chaperones HscA8/Hsp70 as well as HspB8/Hsp22 alone with the co-chaperones Bag3 and STUB1/CHIP (Liu et al., 2013). Importantly, it is found that CASA is essential for muscle maintenance (Arndt et al., 2010). Therefore, HscA8/Hsp70 and HspB8/Hsp22 compex and CASA play an significant function in protein quality control of cancer cells.

Accumulating evidence indicated that autophagy could decide whether cancer cells are promoted or suppressed in certain conditions (Rahman et al., 2020a). In that case, mTOR has an essential function either cellular function becomes an oncogenic activating or protective via inactivation or induction of autophagy pathway (Uddin M. S. et al., 2020; Rahman et al., 2021b). In addition, chemotherapeutic drugs were shown to suppress tumor cells by autophagic modulation (Rahman et al., 2020b). Also, autophagy inhibition has been regulated in cancer progression which decides whether autophagy influences cell death or cell survival function (Jung et al., 2020). Furthermore, epigenetic and genetic function might be alternated the Atgs gene expression which has a greater impact on cancer cell survival. Thus, autophagy modulation of cancer cells has been found to examine the distribution of tumor microenvironment progression which contributes to the potential management and prevention of cancer (Rahman et al., 2020b). Therefore, p53 may react to different kinds of stress as well as damage employed on the cell which comprise endogenous- or environmentally-stressed genotoxicity, oxidative stress, and oncogene activation in order to protect cell damage as well as maintain cellular integrity in cancer (Liu and Gu, 2021). Nevertheless, how posttranslational modifications of p53 postulate its selectivity for each of these transcriptional targets as well as the particular cellular function which induce autophagy in cancer is still unclear.

Cell death regulation is a complicated process of maintaining cellular homeostasis by preventing oncogenic growth and recycling damaged cell debris (Rangel et al., 2021). Dysregulation of autophagic cell death occurs frequently in a variety of malignancies and poses a barrier to current therapy development Rahman et al., 2020. Autophagy plays a critical role in both tumor promotion and suppression. Autophagosomes engulf and digest cell organelles and proteins, which are then recycled to restore homeostasis and cellular metabolism (Duffy et al., 2015). In recent years, it has been proposed that the suppression of autophagy in combination with chemotherapy could be used as an innovative way to treat cancer (Figure 3). Interference with the autophagic machinery, on the other hand, can promote or disrupt carcinogenesis, depending on the type of cancer and their environment. It is, therefore, critical to uncover the primary signaling mechanisms that control carcinogenesis and regulate autophagy (Mrakovcic and Frohlich, 2018). Recently, it has been found that autophagy enhanced the stemness of lung CSCs via degrading ubiquitinated p53, therefore relieving cytosolic p53 inhibition of autophagy through generating stable human lung CSC cell lines of wild-type TP53 (A549) where TP53 has been deleted (H1229) (Wang J. et al., 2021).

The research to date has found several tumor suppressor proteins and oncogenes to be essential regulators of autophagy. The loss or mutation of these proteins contributes to tumor formation. In addition to being one of these tumor suppressors, the mammalian cell “janitor” p53 may be one of the most frequently mutated genes in human tumors. Most human cancers exhibit p53 mutation, which is found in approximately half of all tumors (Soussi and Wiman, 2007; Shi Y. et al., 2020). P53 activation is dependent on various stressors, such as DNA damaging agents, oncogenes, and hypoxia, as well as others, and leads to changes in cell cycling, apoptosis, senescence, metabolism, differentiation, as well as angiogenesis inhibition and autophagy control (Giaccia and Kastan, 1998; Levine and Abrams, 2008). From the results of recent experimental research, it has been ascertained that p53 has both an activator and an inhibitor function with regard to autophagy, depending on its cellular localization and the way of operations (Mrakovcic and Frohlich, 2018). p53 may play a pro-autophagic role in the nucleus, both in a transcription-dependent and independent manner. In the cytoplasm, on the other hand, p53 is known to suppress the induction of autophagy (Maiuri et al., 2010). Recently, it has been highlighted that interplay between pro-inflammatory/pro-oncogenic and pro-inflammatory cytokines pathways regulated via UPR signaling as well as autophagy which affects the stability of p53 that is able to control UPR signaling, cytokine release, and autophagy to preserve its own stability in additional to promote tumorigenesis against cancers carrying mutp53 (D'Orazi et al., 2021).

There are many different cell stressors that might activate p53 (Punja et al., 2021). It is possible that activated p53 may downregulate the autophagy negative regulator, mTOR, through transcriptional regulation of Sestrin1 and Sestrin2, which activate AMPK, which then phosphorylates tuberous sclerosis 2 protein (TSC2) (Budanov and Karin, 2008; Maiuri et al., 2009). In addition to AMPKβ1 and AMPKβ2, p53 can transactivate other AMPKβ subunits including TSC2, PTEN, and IGF-BP3. All of these AMPKβ subunits can be upregulated in response to a stress signal, and upon this elevation, the p53-dependent negative regulation of the mTOR pathways takes place (Feng et al., 2007; Eby et al., 2010). All of these AMPK subunits are capable of being upregulated in response to a stress signal, and this upregulation results in the p53-dependent negative regulation of the mTOR pathways (Jazvinscak Jembrek et al., 2021). A number of targeted genes are activated or inhibited by p53, suggesting that autophagy and cancer prevention are achieved through p53 actions (e.g., activating AMPK and inhibiting mTOR). DRAM (damage-regulated autophagy modulator), a p53 target gene encoding a lysosomal protein that induces macroautophagy, is another mechanism by which p53 promotes the activation of the autophagic pathway. In addition, AEN/ISG20L1 was found to modulate autophagy in response to genotoxic stress by interacting with members of the p53 family (Eby et al., 2010). The three p53 family members (p53, p63, and p73) can regulate transcription of AEN, and downregulation of AEN expression results in decreased levels of autophagic vacuoles and LC3-II, which indicates genotoxic stress. In addition to positive regulators of autophagy, several other pro-apoptotic genes such as PUMA (p53-upregulated modulator of apoptosis) and Bax (Bcl-2-associated X protein) act as autophagy stimulators. It has been discovered that the protein PUMA, which is only found in the mitochondria, induces mitochondrial autophagy. This function of PUMA is distinct from the function of autophagy induced by starvation or ER stress, which is dependent on the presence of the Bax or Bak proteins. Additionally, mitochondrial-selective autophagy can be induced in the absence of PUMA activation in the presence of only Bax (Yee et al., 2009). These pro-apoptotic genes are likely to induce apoptosis and autophagy in a manner that is closely related. Through its direct physical interaction with the BCL-xL receptor, the p53-regulated tumor suppressor protein p14ARF (alternate reading frame protein product of the CDKN2A locus) appears to be able to induce autophagy in human cancer cells (Pimkina et al., 2009; Balaburski et al., 2010). It has been recently confirmed that p14ARF’s tumor suppressive properties are achieved through autophagy activation (Verma et al., 2021). Additionally, the same report resolved previous discrepancies between two p14ARF mRNA isoforms and demonstrated that autophagy can only be induced by the full-length p14ARF mRNA in the nucleus, while mitophagy is induced by smARF (selective macroautophagy of mitochondria) (Ueda et al., 2008; Budina-Kolomets et al., 2013). Studies have found that p53-mediated autophagy begins with DAPK-1 stimulation, with increased gene expression as a secondary response (Zalckvar et al., 2009b). In order to carry out autophagy, DAPK-1 uses two different routes. In the one instance, Beclin-1 phosphorylation inhibits the BCL-2/BCL-xL-mediated degradation of Beclin-1, while in the other, LC3-interacting MAP1B inhibition keeps autophagy from proceeding (Harrison et al., 2008; Zalckvar et al., 2009a).

It has been reported that in p53^−/− cells, only the cytoplasmic p53 can inhibit autophagy through suppressing AMPK and inducing mTOR, resulting in the hyperphosphorylation of AMPK, TSC2, and acetyl CoA carboxylase (ACC) and hypophosphorylation of mTOR substrate, p70S6K (Tasdemir et al., 2008a). Autophagy in HCT116p53^−/−colon carcinoma cells is reduced when they are re-transfected with the p53 wild-type allele. Furthermore, when transfected into p53^−/− cells, p53 mutants that preferentially localize to the cytoplasm are found to effectively repress autophagy (Morselli et al., 2008). According to all of these observations, it is evident that p53 in the cytoplasm inhibits autophagy. It has been previously shown that TIGAR (TP53-induced glycolysis and apoptosis regulator) has a molecular link to p53’s anti-autophagic function (Bensaad et al., 2006). Under stressful conditions, inhibition of autophagy by TIGAR, which is a direct target gene of the tumor suppressor gene p53, has been shown to be associated with downregulation of glycolysis and suppression of ROS formation (Bensaad et al., 2009). When TIGAR’s function is impaired, ROS levels increase, triggering autophagy induction. Nevertheless, it is unlikely to have an effect on the mTOR pathway (Tang et al., 2021a). It is most likely to have a non-mTOR-mediated metabolic pathway as TIGAR does not appear to have a significant impact on mTOR signaling. The interaction of p53 in embryonic carcinoma cells with Beclin-1 leads to the ubiquitination and degradation of the p53, which thus suppresses autophagy (Tripathi et al., 2014). By inhibiting cytoplasmic p53, this effect can be reversed, and autophagy can be induced more effectively.

Cancer cells acquire unique metabolic characteristics to ensure their survival and proliferation (DeBerardinis, 2008). Recent studies have been shown that p53 regulates metabolic traits of cells in addition to its role as a tumor suppressor protein (Wen and Wang, 2021), but the exact mechanism by which p53 regulates metabolism is still not completely understood. As a compensatory response to protect cells against stress, increased signaling triggered by p53 leads to activation of the PtdIns3K-Akt-MAPK-Ras signaling pathway (Corcoran et al., 2006). It was suggested by Gottlieb and Vousden that p53 might be able to counteract the Warburg effect, which is characterized by an abnormally high rate of glycolysis under aerobic conditions and is seen in many cancers (Gottlieb and Vousden, 2010). Recent studies have concluded that p53-regulated metabolism and autophagy are linked which is a primary strategy for cancer treatment to manipulate autophagy regulated by the p53 gene (Shim et al., 2021). A study conducted by Buzzai et al. examined the effect of the anti-diabetic drug metformin on tumor growth in the presence of metformin in the colon cancer cell lines HCT116 p53^+/+ and HCT116p53^−/−, which were isogenic colon cancer cell lines. Autophagy was discovered to be activated in the presence of metformin in HCT116 p53^+/+ cells but not in HCT116 p53^−/− cells in the presence of metformin, which contributed to the continued survival of the cells both in vitro and in vivo (Buzzai et al., 2007; Sui et al., 2011).

Recently, numerous p53-targeting treatment strategies have been established which includings dendritic cell-derived vaccines, adenoviral p53 vectors, p53-degrading E3 ubiquitin ligase inhibitors of Mdm2, and small-molecules to reinstate DNA binding activity. For example, a small molecule multi kinase inhibitor, sunitinib, has been permitted to treat metastatic renal cell carcinoma which degrade autophagic induction of wild type p53 proteins in a multiple cancer cell lines (Luo et al., 2018). Additionally, several synthetic and naturally occurring molecules have been targeted to regulate p53-mediated autophagy regulation in cancer. There are several newly discovered drugs and phytochemicals used as MDM2 inhibitors that have shown potential p53-mediated cancer preventive activities in vitro and in vivo. This section will focus on their efficacy and mechanisms of action.

The role and impact of modulation of p53 in regulation of autophagy is complex and far from fully clarified. Emerging evidence and rapidly developed omics as well as genome editing techniques have likely been to revolutionized a new p53 roles in autophagic activities of different p53 proteins may vary along with changes in tumor microenvironment. Therefore, novel technologies may shed a new perceptions for a knowledge-based insights to recognize gaps-existing knowledge in addition to analyze scenarios which involve a reconsideration for the function of p53 modulation in autophagy signaling in cancer. Recently, autophagy has been established as a dual role in tumor suppression process likely involved in human cancer research. p53 might be an essential player in the modulation of autophagy pathway, although the exact molecular mechanisms and cellular function in cytoplasmic and nuclear p53-mediated autophagy regulation have not been well studied. However, cellular function and role of p53-mediated autophagy, as well as molecular metabolism in cancer progression, require a strongly related and rapidly altering field. The regulation of cancer metabolism by p53 target genes can diverge according to the stress signal, cell type, and other conditions. Additional, it is evidently established that p53 stabilization is a tumor-specific vulnerability, approaches to indorse the degradation of p53 through autophagy which represents an attractive anti-cancer method. Nevertheless, our augmented understanding of the function of p53 and autophagy will hopefully offer a prospective approach to cancer treatment. Therefore, this review revealed that p53 could be targeted as an important implication of cancer therapy via modulation of autophagy signaling. Hitherto the actual therapeutic use of p53-mediated autophagy induction needs detailed knowledge of how the autophagy-lysosomal pathway may affect in cancer progression.