High mobility group box 1 (HMGB1) was originally discovered as a chromatin-binding protein several decades ago. It is now increasingly evident that HMGB1 plays a major role in several disease conditions such as atherosclerosis, diabetes, arthritis, sepsis, and cancer. It is intriguing how deregulation of HMGB1 can result in a myriad of disease conditions. Interestingly, HMGB1 is involved in cell proliferation, angiogenesis, and metastasis during cancer progression. Furthermore, HMGB1 has been demonstrated to exert intracellular and extracellular functions, activating key oncogenic signaling pathways. This paper focuses on the role of HMGB1 in prostate cancer development and highlights the potential of HMGB1 to serve as a key target for prostate cancer treatment. 1. Introduction Current treatment methods for prostate cancer (PCa) such as radical prostatectomy, chemotherapy, radiation therapy, or hormonal therapy are used to effectively manage this disease. However, majority of patients undergoing androgen deprivation therapy develop castration resistant PCa [1]. Hence, there is a great interest in understanding the molecular events that are critical for the development of this disease. If characterized, the genes that play a crucial role in PCa progression or hormone resistance PCa will result in development of novel strategies for treating PCa. Recent evidences strongly suggest that high mobility group box 1 (HMGB1) plays a pivotal role in the development of several cancer types including PCa [2–4]. It is found to be associated with all the hallmarks of cancer development such as cell proliferation, anchorage-independent growth, angiogenesis, migration, and invasion [3]. HMGB1 is a DNA binding protein involved in DNA replication and DNA repair process [5]. Outside the cell, it functions as a proinflammatory cytokine [6]. The extracellular receptors of HMGB1 include RAGE and TLR4, with RAGE being implicated as a major receptor for HMGB1 in tumor development. Deregulation of HMGB1 has been shown to be associated with several inflammation associated diseases such as atherosclerosis [7, 8], arthritis [9], and sepsis [10]. Moreover, HMGB1 is also shown to promote tumorigenesis by inducing inflammation [11, 12]. Inflammation is one of the key risk factors implicated in prostate carcinogenesis [13–15]. Based on the recent published evidences, we highlight and speculate on the role of HMGB1 in PCa development and the potential strategies to target HMGB1 for PCa treatment. 2. HMGB1 Expression in Prostate Cancer Cells: Preclinical and Clinical Samples HMGB1 is
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