TRPM8 channel as a novel molecular target in androgen-regulated prostate cancer cells

Asuthkar, Swapna; Velpula, Kiran Kumar; Elustondo, Pia A.; Demirkhanyan, Lusine; Zakharian, Eleonora

doi:10.18632/oncotarget.3948

Cited by 78 publications

(78 citation statements)

References 45 publications

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“…Consistently with our previous work [8], the proteomic analysis revealed the presence of an initial enzyme of the ubiquitination cascade, UBA1. The UBA1 protein, also called E1, is the ubiquitin-activating enzyme, which requires ATP to form a thioester linkage to ubiquitin [9].…”

Section: Resultssupporting

confidence: 91%

High-throughput proteome analysis reveals targeted TRPM8 degradation in prostate cancer

et al. 2016

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The Ca2+-permeable ion channel TRPM8 is a hallmark of the prostate epithelium. We recently discovered that TRPM8 is an ionotropic testosterone receptor. This finding suggested that testosterone-induced TRPM8 activity regulates Ca2+ homeostasis in the prostate epithelium. Since androgens are significantly implicated in prostate cancer development, the role of the novel testosterone receptor TRPM8 in cancer was assessed in our study. Although TRPM8 mRNA levels increase at the early prostate cancer stages, we found that it is not proportionally translated into TRPM8 protein levels. High-throughput proteome analysis revealed that TRPM8 degradation is enhanced in human prostate cancer cells. This degradation is executed via a dual degradation mechanism with the involvement of both lysosomal and proteasomal proteolytic pathways. The evaluation of the TRPM8 expression pattern in prostate cancer patients further confirmed the incidence of TRPM8 removal from the plasma membrane and its internalization pattern coincided with the severity of the tumor. Together, our results indicate that enhanced TRPM8 hydrolysis in prostate cancer could present an adaptation mechanism, sustained via bypassing testosterone-induced rapid Ca2+ uptake through TRPM8, thus, diminishing the rates of apoptosis. In this light, recovery of TRPM8 may pose a novel therapeutic strategy for an anti-tumor defense mechanism.

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Section: Resultssupporting

confidence: 91%

High-throughput proteome analysis reveals targeted TRPM8 degradation in prostate cancer

et al. 2016

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“…Furthermore, other molecules, including channels such as the transient receptor potential cation channel subfamily M member 8 (TRPM8) (Asuthkar et al . ), and G‐coupled protein receptors such as GPRC6A (Pi et al . ) can be bound, modified and activated by androgens in an AR‐independent fashion.…”

Section: Discussionmentioning

confidence: 99%

“…This is important because, although steroid hormones preferentially engage their specific receptor, there is promiscuity within the steroid hormone ligand-receptor family. Furthermore, other molecules, including channels such as the transient receptor potential cation channel subfamily M member 8 (TRPM8) (Asuthkar et al 2015), and G-coupled protein receptors such as GPRC6A (Pi et al 2015) can be bound, modified and activated by androgens in an AR-independent fashion. Our data conclusively demonstrate that AR function is required for the inhibitory effect.…”

Section: Discussionmentioning

confidence: 99%

Androgens drive microvascular endothelial dysfunction in women with polycystic ovary syndrome: role of the endothelin B receptor

Usselman

Yarovinsky

Steele

et al. 2019

The Journal of Physiology

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Key points Polycystic ovary syndrome (PCOS) is a complex syndrome with cardiovascular risk factors, including obesity and insulin resistance. PCOS is also associated with high androgens, increases the risk of cardiovascular dysfunction in women. Due to the complexity of PCOS, had it has been challenging to isolate specific causes of the cardiovascular dysfunction. Our measure of cardiovascular dysfunction (endothelial dysfunction) was most profound in lean women with PCOS. The endothelin‐1‐induced vasodilation in these PCOS subject, was dependent on the ETBR but was not NO‐dependent. We also demonstrated oestrogen administration improved endothelial function in lean and obese women with PCOS likely because oestrogen increased NO availability. Our studies indicate a primary role for androgens in cardiovascular dysfunction in PCOS. Abstract Endothelin‐1 (ET‐1) is an indicator of endothelial injury and dysfunction and is elevated in women with androgen excess polycystic ovary syndrome (AE‐PCOS). The endothelin B receptor (ETBR) subtype mediates vasodilatation, but is blunted in women with PCOS. We hypothesized that androgen drives endothelial dysfunction in AE‐PCOS women and oestradiol (EE) administration reverses these effects. We assessed microvascular endothelial function in women with (7 lean and 7 obese) and without AE‐PCOS (controls, 6 lean, 7 obese). Only obese AE‐PCOS women were insulin resistant (IR). We evaluated cutaneous vascular conductance (%CVCmax) with laser Doppler flowmetry during low dose intradermal microdialysis ET‐1 perfusions (1, 3, 4, 5 and 7 pmol) with either lactated Ringer solution alone, or with ETBR (BQ‐788), or nitric oxide (NO) inhibition (l‐NAME). Log[ET‐1]–%maxCVC dose–response curves demonstrated reduced vasodilatory responses to ET‐1 in lean AE‐PCOS (logED50, 0.59 ± 0.08) versus lean controls (logED50, 0.49 ± 0.09, P < 0.05), but not compared to obese AE‐PCOS (logED50, 0.65 ± 0.09). ETBR inhibition decreased ET‐1‐induced vasodilatation in AE‐PCOS women (logED50, 0.64 ± 0. 22, P < 0.05). This was mechanistically observed at the cellular level, with ET‐1‐induced, DAF‐FM‐measurable endothelial cell NO production, which was abrogated by dihydrotestosterone in an androgen receptor‐dependent manner. EE augmented the cutaneous vasodilating response to ET‐1(logED50 0.29 ± 0.21, 0.47 ± 0.09, P < 0.05 for lean and obese, respectively). Androgens drive endothelial dysfunction in lean and obese AE‐PCOS. We propose that the attenuated ET‐1‐induced vasodilatation in AE‐PCOS is a consequence of androgen receptor‐mediated, suppressed ETBR‐stimulated NO production, and is reversed with EE.

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“…Also, putative binding sites for p53 were exposed in the TRPM8 promoter, and over-expression of p53 up-regulates the expression of TRPM8 mRNA. 6 In breast cancer, TRPM8 expression appears regulated by the estrogen receptor alpha. 12 In addition, several gene transcription factors such as c-Myc, CREB, and Mef-2 bind to the TRPM8 promoter regions.…”

Section: Discussionmentioning

confidence: 99%

Sustained Morphine Administration Induces TRPM8-Dependent Cold Hyperalgesia

Gong

Jasmin

2017

The Journal of Pain

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It is not uncommon for patients chronically treated with opioids to exhibit opioid induced hyperalgesia (OIH), and this has been widely reported both clinically and experimentally. The molecular substrate for this hyperalgesia is multifaceted, and associated with a complex neural reorganization even in the periphery. For instance, we have recently shown that chronic morphine-induced heat hyperalgesia is associated with an increased expression of GluN2B containing N-methyl-D-aspartate (NMDA) receptors, as well as of the neuronal excitatory amino acid transporter 3/excitatory amino acid carrier 1, in small diameter primary sensory neurons only. Cold allodynia is also a common complaint of patients chronically treated with opioids, yet its molecular mechanisms remain to be understood. Here we present evidence that the cold sensor TRPM8 channel is involved in OIH. After 7 days of morphine administration, we observed an upregulation of TRPM8 channels both by patch clamp recording on sensory neurons and western blot on dorsal root ganglia (DRGs). The selective TRPM8 antagonist RQ-00203078 blocked cold hyperalgesia in morphine treated rats. Also, TRPM8 knockout mice (KO) failed to develop cold hyperalgesia after chronic administration of morphine. Our results demonstrate that chronic morphine upregulates TRPM8 channels, which is in contrast with the previous finding that acute morphine triggers TRPM8 internalization. Perspective Patients receiving chronic opioid are sensitive to cold. We now show in mice and rats that sustained morphine administration induces cold hyperalgesia and an up-regulation of TRPM8. Knockout or selectively blocking TRPM8 reduces morphine induced cold hyperalgesia suggesting TRPM8 is regulated by opioids.

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TRPM8 channel as a novel molecular target in androgen-regulated prostate cancer cells

Cited by 78 publications

References 45 publications

High-throughput proteome analysis reveals targeted TRPM8 degradation in prostate cancer

High-throughput proteome analysis reveals targeted TRPM8 degradation in prostate cancer

Androgens drive microvascular endothelial dysfunction in women with polycystic ovary syndrome: role of the endothelin B receptor

Sustained Morphine Administration Induces TRPM8-Dependent Cold Hyperalgesia

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