Arachidonoyl‐ethanolamide activates endoplasmic reticulum stress‐apoptosis in tumorigenic keratinocytes: Role of cyclooxygenase‐2 and novel J‐series prostamides

Background/Aims: Autophagy plays an essential role in lupus nephritis (LN)-induced kidney injury, although the mechanism of action remains obscure. We investigated the role of cyclooxygenase-2 (COX-2) and the ATF4 endoplasmic reticulum (ER) stress pathway in LN-induced podocyte autophagy. Methods: We evaluated podocyte autophagy in a mouse model of LN. Protein levels of COX-2 and ATF4, and markers of autophagy, were evaluated by immunofluorescence and western blotting. To evaluate apoptosis, levels of PGE2 were measured by enzyme-linked immunosorbent assay. Results: LN induced kidney damage and dysfunction, which was associated with podocyte autophagy. COX-2 and the ATF4 ER stress pathway were induced by LN in cultured podocytes. Inhibition of COX-2 inhibited LN-induced autophagy in podocytes. In addition, blocking ER stress with 4-phenylbutyrate or RNAi partially counteracted COX-2 overexpression and LN-induced autophagy, suggesting that ER stress is required for LN-induced kidney autophagy. Furthermore, LN activated ATF4 and induced its nuclear translocation. Knockdown of ATF4 inhibited LN-induced COX-2 overexpression. Conclusions: Our study suggests a novel molecular mechanism by which COX2 overexpression, induced by the ATF4 ER stress pathway, contributes to LN-induced kidney autophagy and injury. These data demonstrate that COX-2 may be a potential therapeutic target against LN-induced nephropathy.

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“…3C). These results are consistent with other reports that COX-2 is expressed in the perinuclear space in granulocytes [22] and HaCaT cells [23]. …”

Section: Lupus Nephritis Elevates Cox-2 Expression In Podocytessupporting

confidence: 94%

Activation of Cyclooxygenase-2 by ATF4 During Endoplasmic Reticulum Stress Regulates Kidney Podocyte Autophagy Induced by Lupus Nephritis

Jin

Zhao

Zou

et al. 2018

Cell Physiol Biochem

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“…In order to verify that the effect of AEA is not restricted to NMSC cells, additional studies were performed in the human colorectal cell line, HCA‐7. Our previous studies determined that the antitumor activity of AEA is dependent upon COX‐2 ; therefore, we verified that COX‐2 was overexpressed in HCA‐7 cells (Supplemental Figure S3B). To determine whether AEA induced cell death and apoptosis in HCA7 cells, cell viability and caspase 3/7 activity were measured.…”

Section: Resultssupporting

confidence: 69%

“…The endocannabinoid, AEA, is a potential therapeutic for NMSC. Our previous studies showed that AEA selectively induced ER stress‐mediated apoptosis in NMSC cells that overexpress COX‐2 . Specifically, we demonstrated that the cytotoxic effects of AEA were most likely produced by the novel prostaglandin, 15d‐PGJ 2 ‐EA, which was synthesized as a consequence of the metabolism of AEA by COX‐2.…”

Section: Discussionmentioning

confidence: 80%

“…Previous studies from our group showed that the endocannabinoid, AEA selectively induced apoptosis in tumor cells which overexpress COX‐2 due to the conversion of AEA to the novel metabolite, 15 deoxyΔ 12,14 prostaglandin J 2 ‐ethanolamide (15d‐PGJ 2 ‐EA). In addition, we demonstrated that ER stress and oxidative stress were required for AEA‐induced apoptosis . However, the role of oxidative stress and the cannabinoid receptors in AEA‐induced ER stress‐apoptosis was unclear.…”

Section: Introductionmentioning

confidence: 95%

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Anandamide‐induced endoplasmic reticulum stress and apoptosis are mediated by oxidative stress in non‐melanoma skin cancer: Receptor‐independent endocannabinoid signaling

Soliman

Dross

2015

Molecular Carcinogenesis

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Endocannabinoids are neuromodulatory lipids that regulate central and peripheral physiological functions. Endocannabinoids have emerged as effective antitumor drugs due to their ability to induce apoptosis in various cancer studies. The G-protein coupled cannabinoid receptors (CB1 and CB2) and the TRPV1 ion channel were reported to mediate the antiproliferative activity of endocannabinoids. However, receptor-independent effects also account for their activity. Our previous studies showed that the antiproliferative activity of anandamide (AEA) was regulated by cyclooxygenase-2 (COX-2) via induction of endoplasmic reticulum (ER) stress. We also determined that AEA induced oxidative stress. However, the role of oxidative stress, the cannabinoid receptors, and TRPV1 in AEA-induced ER stress-apoptosis was unclear. Therefore, the current study examines the role of oxidative stress in ER stress-apoptosis and investigates whether this effect is modulated by CB1, CB2, or TRPV1. In non-melanoma skin cancer (NMSC) cells, AEA reduced the total intracellular level of glutathione and induced oxidative stress. To evaluate the importance of oxidative stress in AEA-induced cell death, the antioxidants, N-acetylcysteine (NAC) and Trolox, were utilized. Each antioxidant ameliorated the antiproliferative effect of AEA. Furthermore, Trolox inhibited AEA-induced CHOP10 expression and caspase 3 activity, indicating that oxidative stress was required for AEA-induced ER stress-apoptosis. On the other hand, selective blockade of CB1, CB2, and TRPV1 did not inhibit AEA-induced oxidative stress or ER stress-apoptosis. These findings suggest that AEA-induced ER stress-apoptosis in NMSC cells is mediated by oxidative stress through a receptor-independent mechanism. Hence, receptor-independent AEA signaling pathways may be targeted to eliminate NMSC. © 2015 Wiley Periodicals, Inc.

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“…Furthermore, immunofluorescence analysis revealed that COX-2 signals were stronger in the cytoplasm and perinuclear space of Cd-treated cells than in that of control cells (Figure 3f), which was consistent with other reports that COX-2 expressed in the perinuclear space in granulocytes 21 and HaCaT cells. 22 …”

Section: Resultsmentioning

confidence: 99%

Endoplasmic reticulum stress eIF2α–ATF4 pathway-mediated cyclooxygenase-2 induction regulates cadmium-induced autophagy in kidney

et al. 2016

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The heavy metal cadmium (Cd) is nephrotoxic. Recent studies show that autophagy plays an essential role in Cd-induced kidney injury. However, the mechanisms of Cd-induced kidney injury accompanied by autophagy are still obscure. In the present study, we first confirmed that Cd induced kidney damage and dysfunction, along with autophagy, both in vivo and in vitro. Then, we observed that cyclooxygenase-2 (COX-2) and the eIF2α–ATF4 pathway of endoplasmic reticulum (ER) stress were induced by Cd in both kidney tissues and cultured cells. Further studies showed that inhibition of COX-2 with celecoxib or RNA interference (RNAi) inhibited the Cd-induced autophagy in kidney cells. In addition, blocking ER stress with 4-phenylbutyrate or RNAi partially counteracted COX-2 overexpression and autophagy induced by Cd, which suggested that ER stress was required for Cd-induced kidney autophagy. Significantly, our results showed that Cd activated ATF4 and induced its translocation to the nucleus. Knockdown of ATF4 inhibited Cd-induced COX-2 overexpression. While COX-2 overexpression is involved in renal dysfunction, there is no prior report on the role of COX-2 in autophagy regulation. The results of the current study suggest a novel molecular mechanism that the ER stress eIF2α–ATF4 pathway-mediated COX-2 overexpression contributes to Cd-induced kidney autophagy and injury. The present study implies that COX-2 may be a potential target for therapy against Cd-induced nephrotoxicity.

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Arachidonoyl‐ethanolamide activates endoplasmic reticulum stress‐apoptosis in tumorigenic keratinocytes: Role of cyclooxygenase‐2 and novel J‐series prostamides

Cited by 47 publications

References 58 publications

Activation of Cyclooxygenase-2 by ATF4 During Endoplasmic Reticulum Stress Regulates Kidney Podocyte Autophagy Induced by Lupus Nephritis

Activation of Cyclooxygenase-2 by ATF4 During Endoplasmic Reticulum Stress Regulates Kidney Podocyte Autophagy Induced by Lupus Nephritis

Anandamide‐induced endoplasmic reticulum stress and apoptosis are mediated by oxidative stress in non‐melanoma skin cancer: Receptor‐independent endocannabinoid signaling

Endoplasmic reticulum stress eIF2α–ATF4 pathway-mediated cyclooxygenase-2 induction regulates cadmium-induced autophagy in kidney

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