Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells

Xie, Yi; Wang, Linbo; Khan, Mohammad A.; Hamburger, Anne W.; Guang, Wei; Passaniti, Antonino; Munir, Kashif M.; Ross, Douglas D.; Dean, Michael; Hussain, Arif

doi:10.3390/cancers13040633

Cited by 13 publications

(12 citation statements)

References 50 publications

(54 reference statements)

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“…The observed GR-mediated upregulation of LEDGF/p75 in enzalutamide-resistant PCa cells raises the intriguing possibility that this transcription co-activator may also contribute to ARSI resistance. While the most widely accepted mode of action of enzalutamide is targeting AR activity, there is evidence that this drug also triggers apoptosis and attenuates the expression of anti-apoptotic proteins and heat shock proteins such as HSP27 in PCa cells and other cancer cell types [ 103 , 104 , 105 , 106 ]. Targeting anti-apoptotic and cell survival signaling pathways has been proposed as a novel strategy to overcome enzalutamide resistance in PCa [ 18 , 107 , 108 , 109 ].…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells

Sanchez-Hernández

Ochoa

Suzuki

et al. 2023

Cells

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Patients with advanced prostate cancer (PCa) invariably develop resistance to anti-androgen therapy and taxane-based chemotherapy. Glucocorticoid receptor (GR) has been implicated in PCa therapy resistance; however, the mechanisms underlying GR-mediated chemoresistance remain unclear. Lens epithelium-derived growth factor p75 (LEDGF/p75, also known as PSIP1 and DFS70) is a glucocorticoid-induced transcription co-activator implicated in cancer chemoresistance. We investigated the contribution of the GR–LEDGF/p75 axis to docetaxel (DTX)-resistance in PCa cells. GR silencing in DTX-sensitive and -resistant PCa cells decreased LEDGF/p75 expression, and GR upregulation in enzalutamide-resistant cells correlated with increased LEDGF/p75 expression. ChIP-sequencing revealed GR binding sites in the LEDGF/p75 promoter. STRING protein–protein interaction analysis indicated that GR and LEDGF/p75 belong to the same transcriptional network, and immunochemical studies demonstrated their co-immunoprecipitation and co-localization in DTX-resistant cells. The GR modulators exicorilant and relacorilant increased the sensitivity of chemoresistant PCa cells to DTX-induced cell death, and this effect was more pronounced upon LEDGF/p75 silencing. RNA-sequencing of DTX-resistant cells with GR or LEDGF/p75 knockdown revealed a transcriptomic overlap targeting signaling pathways associated with cell survival and proliferation, cancer, and therapy resistance. These studies implicate the GR–LEDGF/p75 axis in PCa therapy resistance and provide a pre-clinical rationale for developing novel therapeutic strategies for advanced PCa.

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Section: Discussionmentioning

confidence: 99%

Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells

Sanchez-Hernández

Ochoa

Suzuki

et al. 2023

Cells

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“…Metformin inhibited 2-deoxyglucose autophagy induction and favored apoptosis [66]. Increased apoptosis was also observed in metformin combined with bicalutamide [94], vitamin D3 [49], curcumin [74], atorvastatin [80], valproic acid [79], abiraterone and enzalutamide [61]. In fact, metformin was shown to reverse resistance to enzalutamide [78].…”

Section: Prostate Cancermentioning

confidence: 95%

“…AR can also suppress AMPK signaling, and inhibition of AMPK signaling prevented metformin-induced AR decrease [59]. Metformin reduced AR and ARv7 (an AR variant correlated with worse prognosis) expression, restoring miR26a-5p expression, which suppressed enhancer of zeste homolog 2 (EZH2), a catalyst of histone-3 lysine 27 trimethylation, that suppressed gene expression and has been correlated with tumor progression [60,61]. Responsiveness to the androgen receptor is a key element in vitro and in vivo.…”

Section: Prostate Cancermentioning

confidence: 99%

Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models

2022

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Metformin is the most used drug for type 2 diabetes (T2DM). Its antitumor activity has been described by clinical studies showing reduced risk of cancer development in T2DM patients, as well as management of T2DM compared with those receiving other glucose-lowering drugs. Metformin has a plethora of molecular actions in cancer cells. This review focused on in vitro data on the action mechanisms of metformin on thyroid, prostate and head and neck cancer. AMPK activation regulating specific downstream targets is a constant antineoplastic activity in different types of cancer; however, AMPK-independent mechanisms are also relevant. In vitro evidence makes it clear that depending on the type of tumor, metformin has different actions; its effects may be modulated by different cell conditions (for instance, presence of HPV infection), or it may regulate tissue-specific factors, such as the Na+/I− symporter (NIS) and androgen receptors. The hallmarks of cancer are a set of functional features acquired by the cell during malignant development. In vitro studies show that metformin regulates almost all the hallmarks of cancer. Interestingly, metformin is one of these therapeutic agents with the potential to synergize with other chemotherapeutic agents, with low cost, low side effects and high positive consequences. Some questions are still challenging: Are metformin in vitro data able to translate from bench to bedside? Does metformin affect drug resistance? Can metformin be used as a generic anticancer drug for all types of tumors? Which are the specific actions of metformin on the peculiarities of each type of cancer? Several clinical trials are in progress or have been concluded for repurposing metformin as an anticancer drug. The continuous efforts in the field and future in vitro studies will be essential to corroborate clinical trials results and to elucidate the raised questions.

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“…Clomipramine and metformin are autophagy inhibitors and have proven to overcome enzalutamide resistance in vitro and in vivo, significantly reducing tumor growth in enza-resistant prostate cancer cells [ 122 ]. In addition, metformin improves the efficacy of both abiraterone and enzalutamide in vitro [ 123 ].…”

Section: Agents and Strategies To Resensitize Crpc To Antiandrogen Th...mentioning

confidence: 99%

Strategies to Re-Sensitize Castration-Resistant Prostate Cancer to Antiandrogen Therapy

et al. 2023

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Since prostate cancer (PCa) was described as androgen-dependent, the androgen receptor (AR) has become the mainstay of its systemic treatment: androgen deprivation therapy (ADT). Although, through recent years, more potent drugs have been incorporated, this chronic AR signaling inhibition inevitably led the tumor to an incurable phase of castration resistance. However, in the castration-resistant status, PCa cells remain highly dependent on the AR signaling axis, and proof of it is that many men with castration-resistant prostate cancer (CRPC) still respond to newer-generation AR signaling inhibitors (ARSis). Nevertheless, this response is limited in time, and soon, the tumor develops adaptive mechanisms that make it again nonresponsive to these treatments. For this reason, researchers are focused on searching for new alternatives to control these nonresponsive tumors, such as: (1) drugs with a different mechanism of action, (2) combination therapies to boost synergies, and (3) agents or strategies to resensitize tumors to previously addressed targets. Taking advantage of the wide variety of mechanisms that promote persistent or reactivated AR signaling in CRPC, many drugs explore this last interesting behavior. In this article, we will review those strategies and drugs that are able to resensitize cancer cells to previously used treatments through the use of “hinge” treatments with the objective of obtaining an oncological benefit. Some examples are: bipolar androgen therapy (BAT) and drugs such as indomethacin, niclosamide, lapatinib, panobinostat, clomipramine, metformin, and antisense oligonucleotides. All of them have shown, in addition to an inhibitory effect on PCa, the rewarding ability to overcome acquired resistance to antiandrogenic agents in CRPC, resensitizing the tumor cells to previously used ARSis.

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Metformin and Androgen Receptor-Axis-Targeted (ARAT) Agents Induce Two PARP-1-Dependent Cell Death Pathways in Androgen-Sensitive Human Prostate Cancer Cells

Cited by 13 publications

References 50 publications

Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells

Glucocorticoid Receptor Regulates and Interacts with LEDGF/p75 to Promote Docetaxel Resistance in Prostate Cancer Cells

Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models

Strategies to Re-Sensitize Castration-Resistant Prostate Cancer to Antiandrogen Therapy

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