Damage-associated molecular pattern (DAMP) activation in melanoma: investigation of the immunogenic activity of 15-deoxy, Δ12,14 prostamide J2

Elhassanny, Ahmed E. M.; Escobedo, Rene; Ladin, Daniel A.; Burns, Colin; Dross, Rukiyah Van

doi:10.18632/oncotarget.27856

Cited by 4 publications

(4 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand, the inhibition of IRE1 or ATF6 did not suppress 15d-PMJ 2 -induced cell death. Moreover, a previous study from our group revealed that PERK was required for ER stress, apoptosis, and the emission of damage associated molecular patterns (DAMPs), which caused dendritic cell maturation [ 42 ]. Hence, our collective findings shed light on the importance of PERK in 15d-PMJ 2 -mediated death and downstream signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

Calcium signaling induced by 15-deoxy-prostamide-J2 promotes cell death by activating PERK, IP3R, and the mitochondrial permeability transition pore

et al. 2022

Self Cite

View full text Add to dashboard Cite

Melanoma is the deadliest form of skin cancer in the US. Although immunotherapeutic checkpoint inhibitors and small-molecule kinase inhibitors have dramatically increased the survival of patients with melanoma, new or optimized therapeutic approaches are still needed to improve outcomes. 15-deoxy-Δ 12,14 -prostamide J 2 (15d-PMJ 2 ) is an investigational small-molecule that induces ER stress-mediated apoptosis selectively in tumor cells. Additionally, 15d-PMJ2 reduces melanoma growth in vivo . To assess the chemotherapeutic potential of 15d-PMJ 2 , the current study sought to uncover molecular pathways by which 15d-PMJ 2 exerts its antitumor activity. B16F10 melanoma and JWF2 squamous cell carcinoma cell lines were cultured in the presence of pharmacological agents that prevent ER or oxidative stress as well as Ca 2+ channel blockers to identify mechanisms of 15d-PMJ 2 cell death. Our data demonstrated the ER stress protein, PERK, was required for 15d-PMJ 2 -induced death. PERK activation triggered the release of ER-resident Ca 2+ through an IP 3 R sensitive pathway. Increased calcium mobilization led to mitochondrial Ca 2+ overload followed by mitochondrial permeability transition pore (mPTP) opening and the deterioration of mitochondrial respiration. Finally, we show the electrophilic double bond located within the cyclopentenone ring of 15d-PMJ 2 was required for its activity. The present study identifies PERK/IP3R/mPTP signaling as a mechanism of 15d-PMJ 2 antitumor activity.

show abstract

Section: Discussionmentioning

confidence: 99%

Calcium signaling induced by 15-deoxy-prostamide-J2 promotes cell death by activating PERK, IP3R, and the mitochondrial permeability transition pore

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…In this context, noteworthy in melanoma would be the emerging cytotoxic role of an endocannabinoid metabolite: 15‐deoxy, Δ12,14 prostamide J2 (15dPMJ2). The latter, acting as a sort of “super‐alarmin” would trigger, in an endoplasmic reticulum stress‐dependent manner, the exposure of damage‐associated molecular patterns (including cell surface CRT, ATP, HMGB1, HSP70 and HSP90) resulting in the recruitment and activation of APCs and activation of the anti‐tumor T cell immune response, thus eliciting an immunogenic cell death response 106 …”

Section: Introductionmentioning

confidence: 99%

“…Promotion of cellular oncogenic events via upregulation of EGFR and EGFR2 and tumor progression via YB-1 and NF-κB activation78 Anti-tumoral Supporting the killing activity of NK cells78 Li Pomi et al79 HMGB1 Pro-tumoral Promotion of neoangiogenesis and pro-tumoral immunity (via IL-10-producing M2 macrophages), upregulation of proinflammatory cytokines IL-23 and IL-17, and suppression of cytotoxic T-cell activity (via the RAGE/HMGB1 axis)79 (Continues)The latter, acting as a sort of "super-alarmin" would trigger, in an endoplasmic reticulum stress-dependent manner, the exposure of damage-associated molecular patterns (including cell surface CRT, ATP, HMGB1, HSP70 and HSP90) resulting in the recruitment and activation of APCs and activation of the anti-tumor T cell immune response, thus eliciting an immunogenic cell death response 106. 2 | DISCUSS IONFrom our critical analysis focusing on the investigated functional role and related clinical importance of each alarmin in cutaneous malignant melanoma so far, a more conclusive view has emerged for some alarmins and so for others.…”

mentioning

confidence: 99%

Alarmins in cutaneous malignant melanoma: An updated overview of emerging evidence on their pathogenetic, diagnostic, prognostic, and therapeutic role

Papa,

Li Pomi,

Borgia

et al. 2024

The Journal of Dermatology

View full text Add to dashboard Cite

Malignant cutaneous melanoma is the leading cause of death for skin cancer to date, with globally increasing incidence rates. In this epidemiological scenario, international scientific research is exerting efforts to identify new clinical strategies aimed at the prognostic amelioration of the disease. Very promising and groundbreaking in this context is the scientific interest related to alarmins and their pioneering utility in the setting of the pathogenetic understanding, diagnosis, prognosis, and therapy for malignant cutaneous melanoma. However, the scientific investigations on this matter should not overlook their still well‐presented dual and contradictory role. The aim of our critical analysis is to provide an up‐to‐date overview of the emerging evidence concerning the dichotomous role of alarmins in the aforementioned clinical settings. Our literature revision was based on the extensive body of both preclinical and clinical findings published on the PubMed database over the past 5 years. In addition to this, we offer a special focus on potentially revolutionary new therapeutic frontiers, which, on the strength of their earliest successes in other clinical areas, could inaugurate a new era of personalized and precision medicine in the field of dermato‐oncology.

show abstract

“…Our group identified a novel molecule produced from the metabolism of AEA by COX-2 named 15-deoxy-Δ 12,14 prostamide J 2 (15d-PMJ 2 ) (Soliman et al, 2016;Ladin et al, 2017). 15d-PMJ 2 activates apoptotic ER stress and ER stress-dependent exposure of damage associated molecular patterns (DAMPs) (Ladin et al, 2022;Elhassanny et al, 2020). The induction of ER stress by 15d-PMJ 2 is primarily mediated by PERK signaling which causes the release of ERresident Ca 2+ and Ca 2+ overload in the mitochondria leading to ER-stress dependent apoptosis (Ladin et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Apoptosis mechanisms induced by 15d-PMJ2 in HCT116 colon cancer cells: insights into CHOP10/TRB3/Akt signaling

Albassam,

Ladin,

Elhassanny

et al. 2023

Front. Pharmacol.

Self Cite

View full text Add to dashboard Cite

Agents that stimulate the endoplasmic reticulum (ER) stress pathway are being exploited pharmacologically to induce cancer cell death. Cytotoxic ER stress is typically regulated by the transcription factor, C/EBP homologous protein 10 (CHOP10). Products of CHOP10 transcription include the pro-apoptotic proteins: ER oxidoreductase 1α (ERO1α), death receptor-5 (DR5), and tribbles-related protein 3 (TRB3). Our previous findings showed cell death induced by 15-deoxy- Δ12,14 prostamide J2 (15d-PMJ2) occurred in an ER stress-dependent manner. However, the pathway by which 15d-PMJ2 regulates ER stress-mediated death downstream of CHOP10 has not been identified. Our results demonstrate 5 µM 15d-PMJ2 increased CHOP10 expression and apoptosis in HCT116 colon cancer cells. In cells treated with pharmacological inhibitors of ER stress, 15d-PMJ2-induced apoptosis was reliant upon the ER stress pathway. To investigate the role of CHOP10 and its transcriptional products in apoptosis, genetic deletion of CHOP10 (CHOP10-KO) was performed using the CRISPR/Cas9 system. The apoptotic action of 15d-PMJ2 was blunted in cells lacking CHOP10 expression. The deletion of CHOP10 reduced the expression of DR5, ERO1α, and TRB3 although only the expression of TRB3 was significantly reduced. Therefore, we overexpressed TRB3 in CHOP10-KO cells and observed that the activation of Akt was inhibited and 15d-PMJ2-induced apoptosis was restored. Thus, a mechanism of apoptosis elicited by 15d-PMJ2 includes the stimulation of CHOP10/TRB3/Akt inhibition. Given the important role these signaling molecules play in cancer cell fate, 15d-PMJ2 may be an effective inducer of apoptosis in cancer cells.

show abstract

Damage-associated molecular pattern (DAMP) activation in melanoma: investigation of the immunogenic activity of 15-deoxy, Δ12,14 prostamide J2

Abstract: Damage-associated molecular pattern (DAMP) activation in melanoma: investigation of the immunogenic activity of 15-deoxy, Δ 12,14 prostamide J 2

Cited by 4 publications

References 36 publications

Calcium signaling induced by 15-deoxy-prostamide-J2 promotes cell death by activating PERK, IP3R, and the mitochondrial permeability transition pore

Calcium signaling induced by 15-deoxy-prostamide-J2 promotes cell death by activating PERK, IP3R, and the mitochondrial permeability transition pore

Alarmins in cutaneous malignant melanoma: An updated overview of emerging evidence on their pathogenetic, diagnostic, prognostic, and therapeutic role

Apoptosis mechanisms induced by 15d-PMJ2 in HCT116 colon cancer cells: insights into CHOP10/TRB3/Akt signaling

Contact Info

Product

Resources

About