Intracellular death platform steps‐in: Targeting prostate tumors via endoplasmic reticulum (ER) apoptosis

Schwarze, Steven R.; Lin, Eric W.; Christian, Perry A.; Gayheart, Dustin; Kyprianou, Natasha

doi:10.1002/pros.20828

Cited by 15 publications

(13 citation statements)

References 88 publications

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“…Recently, ER stress-induced cancer cell apoptosis has become a novel signaling target for the development of cancer therapeutic drugs [ 22 – 24 ]. Various pathological conditions, such as hypoxia, ER-Ca2 + depletion, oxidative injury, hypoglycemia and viral infections, may cause an imbalance between the protein folding load and capacity; this cellular condition is known as ER stress [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Curcumin analog WZ35 induced cell death via ROS-dependent ER stress and G2/M cell cycle arrest in human prostate cancer cells

et al. 2015

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BackgroundProstate cancer is the most commonly diagnosed malignancy among men. The Discovery of new agents for the treatment of prostate cancer is urgently needed. Compound WZ35, a novel analog of the natural product curcumin, exhibited good anti-prostate cancer activity, with an IC50 of 2.2 μM in PC-3 cells. However, the underlying mechanism of WZ35 against prostate cancer cells is still unclear.MethodsHuman prostate cancer PC-3 cells and DU145 cells were treated with WZ35 for further proliferation, apoptosis, cell cycle, and mechanism analyses. NAC and CHOP siRNA were used to validate the role of ROS and ER stress, respectively, in the anti-cancer actions of WZ35.ResultsOur results show that WZ35 exhibited much higher cell growth inhibition than curcumin by inducing ER stress-dependent cell apoptosis in human prostate cells. The reduction of CHOP expression by siRNA partially abrogated WZ35-induced cell apoptosis. WZ35 also dose-dependently induced cell cycle arrest in the G2/M phase. Furthermore, we found that WZ35 treatment for 30 min significantly induced reactive oxygen species (ROS) production in PC-3 cells. Co-treatment with the ROS scavenger NAC completely abrogated the induction of WZ35 on cell apoptosis, ER stress activation, and cell cycle arrest, indicating an upstream role of ROS generation in mediating the anti-cancer effect of WZ35.ConclusionsTaken together, this work presents the novel anticancer candidate WZ35 for the treatment of prostate cancer, and importantly, reveals that increased ROS generation might be an effective strategy in human prostate cancer treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1851-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Curcumin analog WZ35 induced cell death via ROS-dependent ER stress and G2/M cell cycle arrest in human prostate cancer cells

et al. 2015

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“…This is especially significant, since apoptosis due to ERS recently emerged as a strategy for PC treatment. 45,46 The comparison of cytostatic and cytotoxic effects of BZ combinations with FA or CpdA revealed superior potency of CpdA+BZ regimen. Glucocorticoids are known to induce expression of anti-apoptotic and self-defense genes and to desensitize cells against apoptosis by GR.…”

Section: Discussionmentioning

confidence: 99%

Differential targeting of androgen and glucocorticoid receptors induces ER stress and apoptosis in prostate cancer cells

Yemelyanov

Bhalla²,

Yang³

et al. 2012

Cell Cycle

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Androgen (AR) and glucocorticoid (GR) receptor signaling play opposing roles in prostate tumorigenesis: in prostate, AR acts as an oncogene, and GR is a tumor suppressor. Recently, we found that non-steroidal phyto-chemical Compound A (CpdA) is AR/GR modulator acting as anti-inflammatory anti-androgen. CpdA inhibits AR and prevents GR transactivation while enhancing GR transrepression. GR and AR are controlled by proteasomal degradation. We found that prolonged exposure of LNCaP, LNCaP-GR, DU145 and PC3 prostate carcinoma (PCa) cells to proteasome inhibitor Bortezomib (BZ) caused AR degradation and GR accumulation. BZ enhanced CpdA ability to inhibit AR and to augment GR transrepression. We also found that CpdA+BZ differentially regulated GR/AR to cooperatively suppress PCa cell growth and survival and to induce endoplasmic reticulum stress (ERS). Importantly, CpdA+BZ differentially regulated GR-responsive genes. CpdA+BZ blocked activation of glucocorticoid-responsive pro-survival genes, including SGK1, but activated BZ-induced ERS-related genes BIP/HSPA5 and CHOP /GADD153. Using ChIP, we showed that SGK1, BIP/HSPA5 and CHOP regulation was due to effects of CpdA and CpdA+BZ on GR loading on their promoters. We also found that AR and GR are abundant in advanced PCa from patients treated by androgen ablation and/or chemotherapy: 56% of carcinomas from treated patients expressed both receptors, and the other 27% expressed either GR or AR. Overall, our data validate the concept of dual AR/GR targeting in prostate cancer (PC) and suggest that BZ combination with dual-target steroid receptor modulator CpdA has high potential for PC therapy.

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“…it has been suggested that depletion of Ca 2ϩ from ER invokes a number of secondary events like the unfolded protein response (UPR) (2)(3)(4)(5) and activation of store-operated Ca 2ϩ entry (SOCE), flooding the cells with extracellular Ca 2ϩ (6 -8). Eventually, these events are considered to trigger cell death either by cytotoxicity arising from prolonged elevations of [Ca 2ϩ ] i (9 -11) or a stress situation created by Ca 2ϩ depletion from ER, leading to caspase activation and apoptosis (2)(3)(4)(5). However, there is no consensus about the relative importance of these events for the apoptosis induced by Tg: whether it is Ca 2ϩ depletion of ER or an increase in [Ca 2ϩ ] i that is decisive or whether both factors may, in fact, be important for an apoptotic outcome.…”

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confidence: 99%

Inhibition of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase by thapsigargin analogs induces cell death via ER Ca2+ depletion and the unfolded protein response

Sehgal

Szalai

Olesen

et al. 2017

Journal of Biological Chemistry

168

141

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Calcium (Ca) is a fundamental regulator of cell signaling and function. Thapsigargin (Tg) blocks the sarco/endoplasmic reticulum (ER) Ca-ATPase (SERCA), disrupts Ca homeostasis, and causes cell death. However, the exact mechanisms whereby SERCA inhibition induces cell death are incompletely understood. Here, we report that low (0.1 μm) concentrations of Tg and Tg analogs with various long-chain substitutions at the O-8 position extensively inhibit SERCA1a-mediated Ca transport. We also found that, in both prostate and breast cancer cells, exposure to Tg or Tg analogs for 1 day caused extensive drainage of the ER Ca stores. This Ca depletion was followed by markedly reduced cell proliferation rates and morphological changes that developed over 2-4 days and culminated in cell death. Interestingly, these changes were not accompanied by bulk increases in cytosolic Ca levels. Moreover, knockdown of two key store-operated Ca entry (SOCE) components, Orai1 and STIM1, did not reduce Tg cytotoxicity, indicating that SOCE and Ca entry are not critical for Tg-induced cell death. However, we observed a correlation between the abilities of Tg and Tg analogs to deplete ER Ca stores and their detrimental effects on cell viability. Furthermore, caspase activation and cell death were associated with a sustained unfolded protein response. We conclude that ER Ca drainage and sustained unfolded protein response activation are key for initiation of apoptosis at low concentrations of Tg and Tg analogs, whereas high cytosolic Ca levels and SOCE are not required.

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Intracellular death platform steps‐in: Targeting prostate tumors via endoplasmic reticulum (ER) apoptosis

Cited by 15 publications

References 88 publications

Curcumin analog WZ35 induced cell death via ROS-dependent ER stress and G2/M cell cycle arrest in human prostate cancer cells

Curcumin analog WZ35 induced cell death via ROS-dependent ER stress and G2/M cell cycle arrest in human prostate cancer cells

Differential targeting of androgen and glucocorticoid receptors induces ER stress and apoptosis in prostate cancer cells

Inhibition of the sarco/endoplasmic reticulum (ER) Ca2+-ATPase by thapsigargin analogs induces cell death via ER Ca2+ depletion and the unfolded protein response

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