Demethylzeylasteral (T-96) initiates extrinsic apoptosis against prostate cancer cells by inducing ROS-mediated ER stress and suppressing autophagic flux

Yang, Donglin; Zhang, Yajun; He, Liu‐Jun; Hu, Chunsheng; Gao, Lixia; Huang, Jinxiu; Tang, Yan; Luo, Jie; Tang, Dianyong; Chen, Zhongzhu

doi:10.1186/s40659-021-00350-6

Cited by 10 publications

(2 citation statements)

References 66 publications

(74 reference statements)

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“…What's more, it is well-known that excess release of ROS causes ER stress (Celesia et al, 2020). Under oxidative stress conditions, ER stress plays a vital role in the induction of apoptosis and autophagy in various tumors including osteosarcoma (Wang et al, 2019), melanoma (Liu, Kang, et al, 2019), prostate cancer (Yang et al, 2021). Our current results demonstrated that GNA induced ER stress by upregulating the expression levels of p-IRE1, Bip, and CHOP in PCa cells.…”

Section: Discussionsupporting

confidence: 58%

Gambogenic acid induces apoptosis and autophagy through ROS‐mediated endoplasmic reticulum stress via JNK pathway in prostate cancer cells

Wang

Zhou

et al. 2022

Phytotherapy Research

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Prostate cancer (PCa) is the most common malignant tumor in males, which frequently develops into castration‐resistant prostate cancer (CRPC) with limited therapies. Gambogenic acid (GNA), a flavonoids compound isolated from Gamboge, exhibits anti‐tumor capacity in various cancers. Our results showed that GNA revealed not only antiproliferative and pro‐apoptotic activities but also the induction of autophagy in PCa cells. In addition, autophagy inhibitor chloroquine enhanced the pro‐apoptosis effect of GNA. Moreover, the activation of JNK pathway and the induction of apoptosis and autophagy triggered by GNA were attenuated by JNK inhibitor SP600125. We also found that GNA significantly promoted reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress. Meanwhile, suppressing ER stress with 4‐phenylbutyric acid (4‐PBA) markedly blocked the activation of JNK pathway induced by GNA. Further research indicated that ROS scavenger N‐acetyl‐L‐cysteine (NAC) effectively abrogated ER stress and JNK pathway activation induced by GNA. Furthermore, NAC and 4‐PBA significantly reversed GNA‐triggered apoptosis and autophagy. Finally, GNA remarkably suppressed prostate tumor growth with low toxicity in vivo. In conclusion, the present study revealed that GNA induced apoptosis and autophagy through ROS‐mediated ER stress via JNK signaling pathway in PCa cells. Thus, GNA might be a promising therapeutic drug against PCa.

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Section: Discussionsupporting

confidence: 58%

Gambogenic acid induces apoptosis and autophagy through ROS‐mediated endoplasmic reticulum stress via JNK pathway in prostate cancer cells

Wang

Zhou

et al. 2022

Phytotherapy Research

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“… 69 Apart from the compounds mentioned above, other small-molecule compounds that induce apoptosis by targeting TNFR-related proteins are also summarized in Table 1 . 70 – 77 …”

Section: Crucial Signaling Pathways Of Rcd Subroutines In Cancermentioning

confidence: 99%

Regulated cell death (RCD) in cancer: key pathways and targeted therapies

Liao

Qin

et al. 2022

Sig Transduct Target Ther

302

154

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Regulated cell death (RCD), also well-known as programmed cell death (PCD), refers to the form of cell death that can be regulated by a variety of biomacromolecules, which is distinctive from accidental cell death (ACD). Accumulating evidence has revealed that RCD subroutines are the key features of tumorigenesis, which may ultimately lead to the establishment of different potential therapeutic strategies. Hitherto, targeting the subroutines of RCD with pharmacological small-molecule compounds has been emerging as a promising therapeutic avenue, which has rapidly progressed in many types of human cancers. Thus, in this review, we focus on summarizing not only the key apoptotic and autophagy-dependent cell death signaling pathways, but the crucial pathways of other RCD subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis and lysosome-dependent cell death (LCD) in cancer. Moreover, we further discuss the current situation of several small-molecule compounds targeting the different RCD subroutines to improve cancer treatment, such as single-target, dual or multiple-target small-molecule compounds, drug combinations, and some new emerging therapeutic strategies that would together shed new light on future directions to attack cancer cell vulnerabilities with small-molecule drugs targeting RCD for therapeutic purposes.

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Phytochemical‐mediated modulation of autophagy and endoplasmic reticulum stress as a cancer therapeutic approach

Al Azzani,

Nizami,

Magramane

et al. 2024

Phytotherapy Research

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Autophagy and endoplasmic reticulum (ER) stress are conserved processes that generally promote survival, but can induce cell death when physiological thresholds are crossed. The pro‐survival aspects of these processes are exploited by cancer cells for tumor development and progression. Therefore, anticancer drugs targeting autophagy or ER stress to induce cell death and/or block the pro‐survival aspects are being investigated extensively. Consistently, several phytochemicals have been reported to exert their anticancer effects by modulating autophagy and/or ER stress. Various phytochemicals (e.g., celastrol, curcumin, emodin, resveratrol, among others) activate the unfolded protein response to induce ER stress‐mediated apoptosis through different pathways. Similarly, various phytochemicals induce autophagy through different mechanisms (namely mechanistic target of Rapamycin [mTOR] inhibition). However, phytochemical‐induced autophagy can function either as a cytoprotective mechanism or as programmed cell death type II. Interestingly, at times, the same phytochemical (e.g., 6‐gingerol, emodin, shikonin, among others) can induce cytoprotective autophagy or programmed cell death type II depending on cellular contexts, such as cancer type. Although there is well‐documented mechanistic interplay between autophagy and ER stress, only a one‐way modulation was noted with some phytochemicals (carnosol, capsaicin, cryptotanshinone, guangsangon E, kaempferol, and δ‐tocotrienol): ER stress‐dependent autophagy. Plant extracts are sources of potent phytochemicals and while numerous phytochemicals have been investigated in preclinical and clinical studies, the search for novel phytochemicals with anticancer effects is ongoing from plant extracts used in traditional medicine (e.g., Origanum majorana). Nonetheless, the clinical translation of phytochemicals, a promising avenue for cancer therapeutics, is hindered by several limitations that need to be addressed in future studies.

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Demethylzeylasteral (T-96) initiates extrinsic apoptosis against prostate cancer cells by inducing ROS-mediated ER stress and suppressing autophagic flux

Cited by 10 publications

References 66 publications

Gambogenic acid induces apoptosis and autophagy through ROS‐mediated endoplasmic reticulum stress via JNK pathway in prostate cancer cells

Gambogenic acid induces apoptosis and autophagy through ROS‐mediated endoplasmic reticulum stress via JNK pathway in prostate cancer cells

Regulated cell death (RCD) in cancer: key pathways and targeted therapies

Phytochemical‐mediated modulation of autophagy and endoplasmic reticulum stress as a cancer therapeutic approach

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