The tumor suppressor p53 is considered the “guardian of the genome” that can protect cells against cancer by inducing cell cycle arrest followed by cell death. However, STAT3 is constitutively activated in several human cancers and plays crucial roles in promoting cancer cell proliferation and survival. Hence, STAT3 and p53 have opposing roles in cellular pathway regulation, as activation of STAT3 upregulates the survival pathway, whereas p53 triggers the apoptotic pathway. Constitutive activation of STAT3 and gain or loss of p53 function due to mutations are the most frequent events in numerous cancer types. Several studies have reported the association of STAT3 and/or p53 mutations with drug resistance in cancer treatment. This review discusses the relationship between STAT3 and p53 status in cancer, the molecular mechanism underlying the negative regulation of p53 by STAT3, and vice versa. Moreover, it underlines prospective therapies targeting both STAT3 and p53 to enhance chemotherapeutic outcomes.
Cancer is one of the leading causes of death worldwide, which was responsible for approximately 9.6 million cancer deaths in 2018 [1]. Targeted chemotherapy is a common method of cancer treatment in which the molecular pathways related to cancer growth or metastasis are blocked using targeted drugs. Molecularly targeted drugs are less toxic and more effective than conventional drugs because they are administered at lower doses than the higher tolerated dose of the latter [2]. However, both types of drugs suffer from problems associated with cellular resistance, which reduces their efficacy [3]. In addition, chemoresistance is often associated with transformation of tumors into more aggressive and/or metastatic forms.
Signal transduction and activator of transcription (STAT) 3 is a member of the STAT family, comprising seven transcription factors (STAT 1, 2, 3, 4, 5a, 5b, 6) [4]. It was discovered by two independent groups [5,6] and has been of particular interest due to its role in the regulation of cellular signaling, especially in cancers. STAT3 is constitutively active in several cancers such as breast, lung, ovarian, colorectal, cervical, gastric, and prostate cancers, and head and neck squamous cell carcinoma [7,8,9,10,11,12,13]. Despite the multifaceted function of STAT3 in cancer, growing evidence has revealed that constitutive activation of STAT3 contributes to cancer cell proliferation and that aberrant STAT3 activation is associated with tumor malignancy [14,15,16].
TP53 (tumor protein p53) is one of the most well-studied tumor suppressor genes. Owing to its pivotal role in protection against malignancies, wild-type p53 (wtp53) has long been called the “guardian of the genome” [17]. It is well known that p53 suppresses tumor formation and renders protection against DNA damage by inducing cell cycle arrest, DNA repair, or apoptosis [18]. Mutation of p53 is often observed in cancer, especially in late events in malignant progression [19,20].
Tumor cell proliferation and survival involve downregulation of wtp53 expression as well as increase in STAT3 activity. In contrast, wtp53 reduces STAT3 phosphorylation and DNA-binding activity in breast and prostate cancer cells [21,22]. In addition, another report revealed that STAT3 activity suppresses TP53 expression [23]. Therefore, wtp53 and activated STAT3 negatively regulate each other. This adverse regulation can be explained by the opposing biological roles of both factors, as activated STAT3 functions as an oncogene [24], whereas wtp53 functions as a tumor suppressor [25]. Consequently, normal cells might have evolved mechanisms to adjust STAT3 and p53 expression for necessary cell proliferation conditions, whereas tumor cells might exploit such negative regulation for survival [23]. During the early stage of progression, tumors grow preferentially via STAT3-regulated signaling [26]. Although mutations of p53 have been reported to occur early and involve in tumor initiation, it appears that p53 mutations in certain cancers could be developed late and contribute significant roles in advanced stages of tumorigenesis [27]. Furthermore, the loss of wtp53 function along with the accumulation of mutated p53 (mtp53) can support STAT3-mediated tumor cell survival and expansion [28,29,30].
Several inhibitors targeting either STAT3 or p53 are under clinical trials, but their success has been limited because of resistance to targeted cancer therapy [31,32]. Resistance often occurs due to the complexity of cancer signaling pathways, making it difficult for single-target inhibitors to achieve satisfactory clinical outcomes; hence, a combinational therapy co-targeting STAT3 and p53 could overcome drug resistance. The present review provides our current understanding of two well-known targets for cancer therapy, STAT3 and p53, regarding the interaction between them as well as the potential underlying mechanisms. In addition, we have summarized the status of STAT3 and p53 in different cancer cell types and highlighted the potential therapies that target both factors to improve the efficacy of cancer prevention.
Several strategies have been established to inhibit STAT3 signaling, including: (i) downregulating the upstream regulators, (ii) targeting the STAT3 SH2 domain, (iii) blocking the STAT3 DNA-binding domain, (iv) inhibiting the STAT3 N-terminal domain, (v) suppressing the STAT3 mRNA, and (vi) targeting the STAT3 endogenous negative regulators [60]. Direct inhibitors target the SH2 domain (Stattic, S3I-201 and derivatives, OPB-31121, OPB-51602), the DNA-binding domain (Decoy oligonucleotides [ODNs]), the N-terminal domain (ST3-HA2A), or the STAT3 mRNA (AZD9150) to regulate STAT3 activation [61,62,63,64,65,66,67]. Indirect inhibitors target the upstream regulators of the STAT3 signaling pathway (IL-6, RTK, JAK, SRC, BCR-ABL), such as siltuximab, sunitinib, sorafenib, ruxolitinib, bosutinib, or the endogenous STAT3-negative regulators (AdCN305-cppSOCS3 targeting SOCS3) [68,69,70,71,72,73]. The current promising direct STAT3 inhibitors which have entered clinical trials include STAT3 antisense-based AZD9150 (Phase I in hepatocellular carcinoma metastatic, Phase II in advanced cancers), OPB-31121 (Phase I in advanced cancers, phase I/II in hepatocellular carcinoma), OPB-51602 (Phase I in advanced cancers, hematologic malignancies), OPB-111077 (Phase I in solid tumors, leukemia), STAT3 decoy (Early phase I in head and neck cancer).
Feedback activation of STAT3 plays an important role in mediating drug resistance to various conventional chemotherapies and molecularly targeted therapies [32]. The long term activation of tyrosine kinases in malignant tumors can lead to constitutive activation of STAT3, which may not only provide advantages of growth and accumulation of tumor cells, but also confers resistance to conventional therapies that rely on apoptotic machinery to get rid of tumor cells [21]. The downstream outcomes of STAT3 activation supporting tumorigenesis consist of deregulation of cell cycle progression and protection against apoptosis [21]. For example, persistent activation of STAT3 can resist apoptosis in human myeloma cells [74], fibroblasts [75], breast cancer [76], and gastric cancer [13].
As stated above, once activated by phosphorylation at Tyr705, STAT3 forms a dimer and translocates into the nucleus. Hence, drugs targeting the dimeric form of STAT3 are expected to be useful for tumors that rely on STAT3 activation. The SH2 domain is necessary for STAT3 dimer formation and phosphorylation which are recruited to tyrosine-phosphorylated receptor complexes; thus, targeting the SH2 domain is a prospective approach. Some SH2 domain inhibitors have been used in preclinical research (S3I-201 and derivatives) or entered clinical trials (OPB-31121, OPB-51602) for hematologic cancer treatment [77]. However, STAT3 interacts with NF-κB subunits in the absence of Tyr705 phosphorylation or is modified at other sites such as Ser727 to activate transcription [49,78]. It has been reported that nuclear translocation and DNA binding of STAT3 can occur independently of their P-Y status [77]. These observations indicate that SH2 domain-targeting inhibitors may not be adequate to abolish STAT3 oncogenic functions totally, which may become the limitation of these compounds. Therefore, it is obvious that a drug targeting the dimer and its Tyr705 phosphorylation would probably be ineffective if a tumor does not depend solely on the dimeric STAT3 and Tyr705 site for modification.
In brief, several small molecules and inhibitors have been developed and have shown effects in cancer treatment in preclinical research; however, a small number of them could enter clinical trials due to the lack of efficacy issues.
Current strategies targeting p53 in cancer include two types: one targets wtp53 by blocking the degeneration of wtp53 or prolonging its cellular life and disrupting the interaction between wtp53 and its negative regulators MDM2/MDM4; the other targets mtp53 by destabilization of highly accumulated GOF p53 mutants and reactivation of mtp53 via recovery of the wild-type conformation and activity [31,92,93]. Other approaches that indirectly target mtp53 focus on the mtp53-specific downstream signaling pathways, the retaining G2 checkpoint on which a tumor depends, and the mtp53 interactors related to cancer progression [81].
Cancers harboring mtp53 are commonly characterized by serious metastasis and genomic instability; mtp53 is considered a “guardian of the cancer cell” [88]. A variety of p53 mutations produce different oncogenic activities to support tumor development. Generally, mtp53 core activities are recognized as the mirror basal function of the wtp53 counterpart and the adaptive ability to perform oncogenic function. p53 mutations have been linked to chemoresistance in breast, ovarian, lung, gastric, and colorectal cancers [94]. It is not only LOF but also GOF mutation forms that contribute to drug resistance.
The mtp53 confers resistance to different MDM2 inhibitors, as these compounds mainly target wtp53 [95]. Another reason might be that MDM2 inhibitors cannot bind to MDM4, which is an MDM2 homolog with similarities in the N-terminal p53-binding domains; thus, most of the available MDM2 inhibitors lack activity against MDM4 [96]. For example, Nutlin-3a can activate wtp53 in cancer cells overexpressing MDM2 but not in cells overexpressing MDM4 [97]. Another problem with MDM2/MDM4 inhibitors is the unexpected increase in the expression levels of non-MDM2/MDM4 E3 ubiquitin ligases that may degrade wtp53 [98]. These MDM2 inhibitors would be effective mostly in wtp53 tumors because it is possible that p53 pathway restoration disrupts survival pathways and causes cancer cell death, although they also exert hematological toxicity as side effects during clinical trials [99,100]. Therefore, MDM2 antagonists might need to be better developed or used in combination with another method to increase specificity and reduce side effects.
Drug absorption and DNA repair changes are also possible mechanisms causing drug resistance in p53-based cancer therapy. For example, mtp53 stimulates the expression of ABCB1, an ABC transporter, and mediates drug efflux from cells in an ATP-dependent manner, conferring multidrug resistance [94]. Furthermore, p53 mutants disrupt critical DNA damage response pathways by interfering with binding of the MRE11–RAD50–NBS1 complex to the site of DNA damage, resulting in ataxia telangiectasia mutated (ATM) inactivation and genetic instability [101]. Notably, mtp53 recruits poly(ADP-ribose) polymerase 1 (PARP1), MCM4, and proliferating cell nuclear antigen (PCNA) to change chromatin structure and thus negatively regulates DNA repair while still allowing DNA replication to increase in breast cancer cells [102]. From these observations, it can be inferred that the indirect p53 inhibition approach could not satisfy drug treatment outcomes; hence, there is a need for a combination method that directly targets mtp53 as well as cancer-specific activation mechanisms.
This entry is adapted from the peer-reviewed paper 10.3390/biomedicines8120637