STAT3 Pathway in Cancers: Past, Present, and Future

Overview

Journal MedComm (2020)

Specialty Health Services

Date 2022 Mar 31

PMID 35356799

Authors

Han-Qi Wang

Qi-Wen Man

Fang-Yi Huo

Xin Gao

Hao Lin

Su-Ran Li

Jing Wang

Fu-Chuan Su

Lulu Cai

Yi Shi

Bing Liu

Lin-Lin Bu

Affiliations

Soon will be listed here.

Abstract

Signal transducer and activator of transcription 3 (STAT3), a member of the STAT family, discovered in the cytoplasm of almost all types of mammalian cells, plays a significant role in biological functions. The duration of STAT3 activation in normal tissues is a transient event and is strictly regulated. However, in cancer tissues, STAT3 is activated in an aberrant manner and is induced by certain cytokines. The continuous activation of STAT3 regulates the expression of downstream proteins associated with the formation, progression, and metastasis of cancers. Thus, elucidating the mechanisms of STAT3 regulation and designing inhibitors targeting the STAT3 pathway are considered promising strategies for cancer treatment. This review aims to introduce the history, research advances, and prospects concerning the STAT3 pathway in cancer. We review the mechanisms of STAT3 pathway regulation and the consequent cancer hallmarks associated with tumor biology that are induced by the STAT3 pathway. Moreover, we summarize the emerging development of inhibitors that target the STAT3 pathway and novel drug delivery systems for delivering these inhibitors. The barriers against targeting the STAT3 pathway, the focus of future research on promising targets in the STAT3 pathway, and our perspective on the overall utility of STAT3 pathway inhibitors in cancer treatment are also discussed.

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References

Miyoshi K, Takaishi M, Nakajima K, Ikeda M, Kanda T, Tarutani M . Stat3 as a therapeutic target for the treatment of psoriasis: a clinical feasibility study with STA-21, a Stat3 inhibitor. J Invest Dermatol. 2010; 131(1):108-17. DOI: 10.1038/jid.2010.255. View

Huang W, Dong Z, Wang F, Peng H, Liu J, Zhang J . A small molecule compound targeting STAT3 DNA-binding domain inhibits cancer cell proliferation, migration, and invasion. ACS Chem Biol. 2014; 9(5):1188-96. PMC: 4033648. DOI: 10.1021/cb500071v. View

Attili I, Karachaliou N, Bonanno L, Berenguer J, Bracht J, Codony-Servat J . STAT3 as a potential immunotherapy biomarker in oncogene-addicted non-small cell lung cancer. Ther Adv Med Oncol. 2018; 10:1758835918763744. PMC: 5888808. DOI: 10.1177/1758835918763744. View

Hong D, Kurzrock R, Kim Y, Woessner R, Younes A, Nemunaitis J . AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci Transl Med. 2015; 7(314):314ra185. PMC: 5279222. DOI: 10.1126/scitranslmed.aac5272. View

Durham G, Williams J, Nasim M, Palmer T . Targeting SOCS Proteins to Control JAK-STAT Signalling in Disease. Trends Pharmacol Sci. 2019; 40(5):298-308. DOI: 10.1016/j.tips.2019.03.001. View

Roy R, Dagher A, Butterfield C, Moses M . ADAM12 Is a Novel Regulator of Tumor Angiogenesis via STAT3 Signaling. Mol Cancer Res. 2017; 15(11):1608-1622. PMC: 5668165. DOI: 10.1158/1541-7786.MCR-17-0188. View

Mohammadian J, Mahmoudi S, Pourmohammad P, Pirouzpanah M, Salehnia F, Maroufi N . Formulation of Stattic as STAT3 inhibitor in nanostructured lipid carriers (NLCs) enhances efficacy of doxorubicin in melanoma cancer cells. Naunyn Schmiedebergs Arch Pharmacol. 2020; 393(12):2315-2323. DOI: 10.1007/s00210-020-01942-x. View

Chan H, Shan H, Dahoun T, Vogel H, Yuan S . Advancing Drug Discovery via Artificial Intelligence. Trends Pharmacol Sci. 2019; 40(8):592-604. DOI: 10.1016/j.tips.2019.06.004. View

Fan Y, Mao R, Yang J . NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell. 2013; 4(3):176-85. PMC: 4875500. DOI: 10.1007/s13238-013-2084-3. View

10.

Lee E, Harris T, Tran S, Evangelista M, Arulananda S, John T . BCL-XL and MCL-1 are the key BCL-2 family proteins in melanoma cell survival. Cell Death Dis. 2019; 10(5):342. PMC: 6482196. DOI: 10.1038/s41419-019-1568-3. View

11.

Leung C, Chan D, Ma V, Ma D . DNA-binding small molecules as inhibitors of transcription factors. Med Res Rev. 2012; 33(4):823-46. DOI: 10.1002/med.21266. View

12.

Molavi O, Ma Z, Mahmud A, Alshamsan A, Samuel J, Lai R . Polymeric micelles for the solubilization and delivery of STAT3 inhibitor cucurbitacins in solid tumors. Int J Pharm. 2007; 347(1-2):118-27. PMC: 2663961. DOI: 10.1016/j.ijpharm.2007.06.032. View

13.

Luo K, Gao Y, Yin S, Yao Y, Yu H, Wang G . Co-delivery of paclitaxel and STAT3 siRNA by a multifunctional nanocomplex for targeted treatment of metastatic breast cancer. Acta Biomater. 2021; 134:649-663. DOI: 10.1016/j.actbio.2021.07.029. View

14.

Zhang W, Zhang J, Zhang Z, Guo Y, Wu Y, Wang R . Overexpression of Indoleamine 2,3-Dioxygenase 1 Promotes Epithelial-Mesenchymal Transition by Activation of the IL-6/STAT3/PD-L1 Pathway in Bladder Cancer. Transl Oncol. 2018; 12(3):485-492. PMC: 6307990. DOI: 10.1016/j.tranon.2018.11.012. View

15.

Gaykalova D, Manola J, Ozawa H, Zizkova V, Morton K, Bishop J . NF-κB and stat3 transcription factor signatures differentiate HPV-positive and HPV-negative head and neck squamous cell carcinoma. Int J Cancer. 2015; 137(8):1879-89. PMC: 4629062. DOI: 10.1002/ijc.29558. View

16.

Zhang T, Kee W, Seow K, Fung W, Cao X . The coiled-coil domain of Stat3 is essential for its SH2 domain-mediated receptor binding and subsequent activation induced by epidermal growth factor and interleukin-6. Mol Cell Biol. 2000; 20(19):7132-9. PMC: 86266. DOI: 10.1128/MCB.20.19.7132-7139.2000. View

17.

Chen H, Bian A, Yang L, Yin X, Wang J, Ti C . Targeting STAT3 by a small molecule suppresses pancreatic cancer progression. Oncogene. 2021; 40(8):1440-1457. PMC: 7906907. DOI: 10.1038/s41388-020-01626-z. View

18.

Yang J, Lu R, Ye X, Zhang J, Tan Y, Zhou G . Icaritin Reduces Oral Squamous Cell Carcinoma Progression via the Inhibition of STAT3 Signaling. Int J Mol Sci. 2017; 18(1). PMC: 5297765. DOI: 10.3390/ijms18010132. View

19.

Park S, Jang W, Yi E, Jang J, Jung Y, Jeong J . Melatonin suppresses tumor angiogenesis by inhibiting HIF-1alpha stabilization under hypoxia. J Pineal Res. 2010; 48(2):178-84. DOI: 10.1111/j.1600-079x.2009.00742.x. View

20.

Chang Y, Liu T, Liu S, Tseng C . Arecoline inhibits myogenic differentiation of C2C12 myoblasts by reducing STAT3 phosphorylation. Food Chem Toxicol. 2012; 50(10):3433-9. DOI: 10.1016/j.fct.2012.07.032. View