Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

Abstract

Cancer is one of the most common causes of death worldwide, and its development is a result of the complex interaction of genetic factors, environmental cues, and aging. Hormone-sensitive cancers depend on the action of one or more hormones for their development and progression. Sex steroids and corticosteroids can regulate different physiological functions, including metabolism, growth, and proliferation, through their interaction with specific nuclear receptors, that can transcriptionally regulate target genes via their genomic actions. Therefore, interference with hormones’ activities, e.g., deregulation of their production and downstream pathways or the exposition to exogenous hormone-active substances such as endocrine-disrupting chemicals (EDCs), can affect the regulation of their correlated pathways and trigger the neoplastic transformation. Although nuclear receptors account for most hormone-related biologic effects and their slow genomic responses are well-studied, less-known membrane receptors are emerging for their ability to mediate steroid hormones effects through the activation of rapid non-genomic responses also involved in the development of hormone-sensitive cancers. This review aims to collect pre-clinical and clinical data on these extranuclear receptors not only to draw attention to their emerging role in cancer development and progression but also to highlight their dual role as tumor microenvironment players and potential candidate drug targets.

Endocrine Disruptors and Prostate Cancer

“…In PCa, GPCR6A is expressed at high levels, and it is correlated with increased tumor size, distant metastasis and tumor recurrence [14,68]. Indeed, in AR-independent PCa, GPRC6A overexpression has been demonstrated to mediate rapid, non-genomic signaling in response to androgen binding [70,71]. Computational studies have demonstrated the ability of androgens, in particular testosterone, to bind GPRC6A and in vitro it has been shown that such a binding leads to ERK1/2 phosphorylation and activation and to a decreased expression of the tumor-suppressor Early Growth Response Protein 1 [72].…”

“…Moreover, T binding to GPRC6A can lead to the activation of Akt and mammalian Target of Rapamycin (mTOR) signaling pathways resulting in an increased cell proliferation and inhibition of autophagy in PCa [73]. It is worth noting that in Asian populations the association between GPRC6A gene and PCa risk has been reported [70] and even a specific polymorphism (rs2274911) in GPRC6A has been associated with an increased PCa risk, since this mutation promotes cell proliferation and is associated with increased PSA serum levels [71].…”

“…ZIP9/SLC39A9 is a zinc-importing protein belonging to a 14-member family regulating zinc transport from the extracellular space to the cytoplasm [13,14]. ZIP9 is a dual function protein acting both as a Zn 2+ transporter and as a mAR: this dual role is exerted through G proteins involved in apoptotic pathways activated by androgens [13,14,70]. ZIP9 has been demonstrated to possess high binding affinity with T, while other endogenous androgens such as androstenedione and DHT display low affinity [14,70].…”

“…ZIP9 is a dual function protein acting both as a Zn 2+ transporter and as a mAR: this dual role is exerted through G proteins involved in apoptotic pathways activated by androgens [13,14,70]. ZIP9 has been demonstrated to possess high binding affinity with T, while other endogenous androgens such as androstenedione and DHT display low affinity [14,70]. ZIP9 has been demonstrated to be highly expressed and bound by androgens in ovarian, breast, and PCa cells, the same hormone-sensitive tumors in which testosterone has been demonstrated to increase intracellular Zn 2+ , where it led to high Zn 2+ concentration-mediated apoptosis [13].…”

Cellular Senescence in Age-Related Diseases: Molecular Bases and Therapeutic Interventions

“…Membrane progesterone receptors that mediate nontraditional progesterone actions are classified into two groups: the class II progestin and adipoQ receptor (PAQR) family (also called membrane progesterone receptors, mPRs) and the b5-like haem/steroidbinding protein family (also called membrane-associated progesterone receptors, MAPRs). To elucidate the role of these membrane receptors as key players in shaping the cancer environment and, therefore, as potential drug targets, Masi and collaborators showed the membrane receptors' pivotal role in mediating the effects of steroid hormones and hormone-active substances in both physiologic and pathologic contexts by collecting preclinical and clinical data; thus, providing the first critical and in-depth view in the context of hormone-sensitive cancers [12].…”