bims-istrec 2021-12-19 papers

Issue of 2021‒12‒19
three papers selected by
Vincenzo Ciminale’s Lab
Istituto Oncologico Veneto

Acta Pharm Sin B. 2021 Nov;11(11): 3567-3584

Discovery of a small molecule inhibitor of cullin neddylation that triggers ER stress to induce autophagy.

Yanan Li, Chaorong Wang, Tiantian Xu, Peichen Pan, Qing Yu, Lei Xu, Xiufang Xiong, Tingjun Hou, Sunliang Cui, Yi Sun.

Protein neddylation is catalyzed by a three-enzyme cascade, namely an E1 NEDD8-activating enzyme (NAE), one of two E2 NEDD8 conjugation enzymes and one of several E3 NEDD8 ligases. The physiological substrates of neddylation are the family members of cullin, the scaffold component of cullin RING ligases (CRLs). Currently, a potent E1 inhibitor, MLN4924, also known as pevonedistat, is in several clinical trials for anti-cancer therapy. Here we report the discovery, through virtual screening and structural modifications, of a small molecule compound HA-1141 that directly binds to NAE in both in vitro and in vivo assays and effectively inhibits neddylation of cullins 1-5. Surprisingly, unlike MLN4924, HA-1141 also triggers non-canonical endoplasmic reticulum (ER) stress and PKR-mediated terminal integrated stress response (ISR) to activate ATF4 at an early stage, and to inhibit protein synthesis and mTORC1 activity at a later stage, eventually leading to autophagy induction. Biologically, HA-1141 suppresses growth and survival of cultured lung cancer cells and tumor growth in in vivo xenograft lung cancer models at a well-tolerated dose. Taken together, our study has identified a small molecule compound with the dual activities of blocking neddylation and triggering ER stress, leading to growth suppression of cancer cells.

Keywords: Autophagy; Cullin RING ligase; ER stress; Neddylation; Small molecule inhibitor; mTORC1

DOI: https://doi.org/10.1016/j.apsb.2021.07.012

J Int Med Res. 2021 Dec;49(12): 3000605211065376

Levels of endoplasmic reticulum stress-related mRNA in peritoneal fluid of patients with endometriosis or gynaecological cancer.

Seung Geun Yeo, Sung Jong Lee, Ji Woo Lee, Sujung Oh, Dong Choon Park.

OBJECTIVE: To compare the levels of endoplasmic reticulum (ER) stress-associated mRNAs and the clinical characteristics of patients with endometriosis or gynaecological cancer.METHODS: This prospective study obtained intraperitoneal fluid samples from female patients that underwent surgery. The levels of ER stress mRNAs in the peritoneal fluid, including C/EBP-homologous protein (CHOP), X-box binding protein 1 (sXBP1), activating transcription factor 6 (ATF6), immunoglobulin heavy chain-binding protein (BiP), inositol-requiring enzyme 1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK), were measured using real-time reverse transcription-polymerase chain reaction in patients with benign disease without endometriosis (control group), with endometriosis or with gynaecological cancer.
RESULTS: This study enrolled 126 patients: 46 control patients; 47 with endometriosis; and 33 with cancer. The levels of CHOP and BiP mRNA were significantly higher in the control group compared with the cancer group. Levels of sXBP1 and ATF6 mRNA were significantly higher in the cancer group than in the control and endometriosis groups. In the endometriosis group, ATF6 mRNA level was inversely correlated with age and positively correlated with serum cancer antigen 125 levels; and ATF6 and PERK mRNA levels were inversely correlated with parity.
CONCLUSION: The levels of ER stress-related mRNAs were related to the pathogenesis of endometriosis and gynaecological cancers.

Keywords: Endoplasmic reticulum stress-related mRNA; endometriosis; gynaecological cancer

DOI: https://doi.org/10.1177/03000605211065376

Front Pharmacol. 2021 ;12 714163

Sini San Inhibits Chronic Psychological Stress-Induced Breast Cancer Stemness by Suppressing Cortisol-Mediated GRP78 Activation.

Yifeng Zheng, Juping Zhang, Wanqing Huang, Linda L D Zhong, Neng Wang, Shengqi Wang, Bowen Yang, Xuan Wang, Bo Pan, Honglin Situ, Yi Lin, Xiaoyan Liu, Yafei Shi, Zhiyu Wang.

Chronic psychological stress is closely correlated with breast cancer growth and metastasis. Sini San (SNS) formula is a classical prescription for relieving depression-related symptoms in traditional Chinese medicine (TCM). Current researches have suggested that chronic psychological stress is closely correlated with cancer stem cells (CSCs) and endoplasmic reticulum (ER) stress. This study aimed to investigate the effects of chronic psychological stress on ER stress-mediated breast cancer stemness and the therapeutic implication of SNS. Chronic psychological stress promoted lung metastasis in 4T1 breast tumor-bearing mice and increased the stem cell-like populations and stemness-related gene expression. Meanwhile, GRP78, a marker of ER stress, was significantly increased in the breast tumors and lung metastases under chronic psychological stress. As a biochemical hallmark of chronic psychological stress, cortisol dramatically enhanced the stem cell-like populations and mammospheres formation by activating GRP78 transcriptionally. However, GRP78 inhibitors or shRNA attenuated the stemness enhancement mediated by cortisol. Similarly, SNS inhibited chronic psychological stress-induced lung metastasis and stemness of breast cancer cells, as well as reversed cortisol-induced stem cell-like populations and mammospheres formation by attenuating GRP78 expression. Co-localization and co-immunoprecipitation experiments showed that SNS interrupted the interaction between GRP78 and LRP5 on the cell surface, thus inhibiting the Wnt/β-catenin signaling of breast CSCs. Altogether, this study not only uncovers the biological influence and molecular mechanism of chronic psychological stress on breast CSCs but also highlights SNS as a promising strategy for relieving GRP78-induced breast cancer stemness via inhibiting GRP78 activation.

Keywords: GRP78/LRP5; Sini San; breast cancer stem cells; chronic psychological stress; cortisol

DOI: https://doi.org/10.3389/fphar.2021.714163