The role of hypoxia on prostate cancer progression and metastasis

Abstract

Prostate cancer is the second most common cancer diagnosed in men and the fifth-leading cause of cancer death in men worldwide. Like any solid tumor, the hypoxic microenvironment of prostatic cancer drives hypoxia-inducible factors (HIFs) to mediate cell adaptions to hypoxic conditions. HIFs direct different signaling pathways such as PI3K/Akt/mTOR, NOX, and Wnt/β-Catenin to tumor progression depending on the degree of hypoxia. HIFs regulate cytoskeleton protein expression, promoting epithelial-mesenchymal transition (EMT), which occurs when cancer cells lose cell-to-cell adhesions and start invasion and metastasis. Through activating pathways, the hypoxic microenvironment maintains the self-renewal, potency, and anti-apoptotic function of prostate cancer cells and induces tumor metastasis and transformation. These pathways could serve as a potential target for prostate cancer therapy. HIFs increase the expression of androgen receptors on cancer cells maintaining the growth and survival of prostate cancer and the development of its castration resistance. In this review, we elaborate on the role of hypoxia in prostatic cancer pathogenesis and different hypoxia-induced mechanisms.

Chronic hypoxia stabilizes 3βHSD1 via autophagy suppression

“… 28 , 56 Prostate tumor is highly hypoxic, and hypoxia plays a critical role in treatment resistance and metastasis. 19 , 24 , 25 , 27 , 28 , 57 Therefore, our HR cell lines, which can survive under hypoxia indefinitely, may better simulate the hypoxic conditions that exist in a tumor.…”

Understanding human aging and the fundamental cell signaling link in age-related diseases: the middle-aging hypovascularity hypoxia hypothesis

“…Loss of micro-vascularity ( Hofer and Morey, 2018 ; Gerbie et al, 2021 ) implies an important role for cyclic/chronic hypoxic milieu ( Fine and Norman, 2008 ) in regionalizing perfusion and contributing to the progression of age-related degenerative comorbid diseases in humans. Age-related declining sex hormones (andropause/menopause) are mediated by NO–oxygen sensing ( Berchner-Pfannschmidt et al, 2007 ; Hickok et al, 2013 ), causing a hypoxic stress condition and dysregulation of the cellular biology of amyloidosis ( Cheboub et al, 2019 ; Ahmed et al, 2022 ), which is counteracted by autophagy ( Chuang et al, 2018 ; Wang and Le, 2019 ; Wang and Zhang, 2019 ), along with the epithelial-to-mesenchymal transition (EMT) ( Byrne et al, 2016 ; Kim I. et al, 2022 ; Ribatti, 2022 ; Mohamed et al, 2023 ). A regionally restricted oxygen perfusion is a cyclic/chronic hypoxic environment that can lead to degenerative pathologies such as hypertrophy, atrophy, fibrosis, and neoplasm due to developing localized hypoxia ( Figure 1 ).…”

“…Examples of such a range of hypoxic degenerative pathologies can be seen in acute high-altitude hypoxia (hypobaric hypoxia) organ hypertrophy ( Pena et al, 2022 ) and tissue edema ( Mesentier-Louro et al, 2021 ). Others include androgen deprivation therapy promoting epithelial–mesenchymal transition ( Byrne et al, 2016 ), cancer-associated fibroblasts ( Kim I. et al, 2022 ), and prostate cancer progression metastasis ( Mohamed et al, 2023 ).…”

Pharmacological Significance of Heme Oxygenase 1 in Prostate Cancer

“…Since anti-inflammatory and anticarcinogenic drugs have the ability to activate the Nrf2/ARE/electrophile-responsive element (EpRE) cytoprotective pathways while inhibiting NF-κB signaling, alpha tocopheryl succinate (α-TOS)-induced ROS production affected the upregulation of Nrf2-driven genes leading to the suppression of NF-κB in the PCa cell line [4]. Hypoxia plays a fundamental role in PCa development, progression, and metastasis [61,62]. Several signaling pathways are activated under the hypoxic microenvironment of PCa.…”