bims-istrec 2022-05-08 papers

Issue of 2022‒05‒08
four papers selected by
Vincenzo Ciminale’s Lab
Istituto Oncologico Veneto

Cancer Discov. 2022 May 06. OF1

Ceramide Accumulation Induces the Integrated Stress Response in AML.

High ceramide levels promote the apoptotic integrated stress response in acute myeloid leukemia (AML).

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-083

J Hepatocell Carcinoma. 2022 ;9 327-341

Protodioscin Induces Mitochondrial Apoptosis of Human Hepatocellular Carcinoma Cells Through Eliciting ER Stress-Mediated IP3R Targeting Mfn1/Bak Expression.

Chen-Lin Yu, Hsiang-Lin Lee, Shun-Fa Yang, Shih-Wei Wang, Ching-Pin Lin, Yi-Hsien Hsieh, Hui-Ling Chiou.

Objective: Protodioscin (PD), a steroidal saponin, has a diverse pharmacological activity including neuroprotection, male fertility improvement, and cytotoxicity against various cancers cell lines of different origins. However, the effect of PD on hepatocellular carcinoma (HCC) is still unclear.Methods: Cell viability, colony formation and flow cytometry analysis for apoptosis profile, mitochondrial membrane potential endoplasmic reticulum (ER) expansion were employed to determine the effect of PD against HCC cells. Transient transfection of siRNA, immunofluorescent imaging and immunoprecipitation were used to elucidate the anti-cancer mechanism of PD. The in vivo toxicity and efficacy of PD were assessed by a xenograft mouse model.
Results: PD induced apoptosis, loss of mitochondrial membrane potential and ER expansion in HCC cells. Either downregulation of Mfn1 or Bak reversed PD-induced apoptosis and loss of mitochondrial membrane potential. Further analysis revealed that Mfn1 and Bak will form a complex with IP3R to facilitate the transfer of Ca2+ from ER to mitochondria and apoptosis. In addition, our tumour xenograft model further verifies the in vivo anti-tumour effect of PD.
Conclusion: Our study sheds light on the understanding of the anti-HCC effects of PD and may open new aspects for the development of novel treatment for human hepatocellular carcinoma.

Keywords: apoptosis; endoplasmic reticulum; hepatocellular carcinoma; mitochondrial; protodioscin

DOI: https://doi.org/10.2147/JHC.S355027

Front Oncol. 2022 ;12 824043

Z-Ligustilide Induces c-Myc-Dependent Apoptosis via Activation of ER-Stress Signaling in Hypoxic Oral Cancer Cells.

Ren-Jun Hsu, Kui-Yuan Peng, Wen-Lin Hsu, Yu-Tang Chen, Dai-Wei Liu.

Z-ligustilide (or ligustilide) is found in Angelica sinensis (Oliv.) Diels and may exert potential benefits in cancer treatment. Previous research has reported that ligustilide has anti-cancer effects on several types of cancer cells. However, studies of ligustilide on oral cancer cells have not been reported, especially under hypoxic conditions. This study focuses on the molecular mechanism of ligustilide-induced apoptosis in hypoxic oral cancer cells. We found that in hypoxic TW2.6 cells, ligustilide inhibited cell migration and induced caspase-dependent apoptosis. Accumulation of c-Myc accompanied by BH3-only members suggests that ligustilide may induce c-Myc-dependent apoptosis. In addition, we reported that ligustilide has an effect on ER-stress signaling. By using inhibitors of c-Myc, IRE1α, and ER-stress inhibitors, we found that cell morphologies or cell viability were rescued to some degree. Moreover, ligustilide is able to increase the expression of γ-H2AX and enhance the occurrence of DNA damage in oral cancer cells after radiation treatment. This result suggests that ligustilide has potential as a radiation sensitizer. Altogether, we propose that ligustilide may induce c-Myc-dependent apoptosis via ER-stress signaling in hypoxic oral cancer cells.

Keywords: ER stress; Z-ligustilide (LIG); c-Myc; oral cancer cells; radiosensitizer

DOI: https://doi.org/10.3389/fonc.2022.824043

Mol Ther. 2022 May 05. pii: S1525-0016(22)00293-3. [Epub ahead of print]

KLF16 enhances stress tolerance of colorectal carcinomas by modulating nucleolar homeostasis and translational reprogramming.

Xiao-Dan Ma, Shui-Dan Xu, Shi-Hui Hao, Kai Han, Jie-Wei Chen, Han Ling, Ri-Xin Chen, Xiao-Han Jin, Jing-Hua Cao, Jin-Long Lin, Qing-Jian Ou, Yu-Jing Fang, Zhi-Zhong Pan, Dan Xie, Feng-Wei Wang.

Translational reprogramming is part of the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress, which acts to the advantage of cancer growth and development in different stress conditions. But the mechanism of ER stress-related translational reprogramming in colorectal carcinoma (CRC) progression remains unclear. Here, we identified that Krüppel-Like Factor 16 (KLF16) can promote CRC progression and stress tolerance through translational reprogramming. The expression of KLF16 was upregulated in CRC tissues and associated with poor prognosis for CRC patients. We found that ER stress inducers can recruit KLF16 to the nucleolus and increase its interaction with two essential proteins for nucleolar homeostasis, nucleophosmin1 (NPM1) and fibrillarin (FBL). Moreover, knockdown of KLF16 can dysregulate nucleolar homeostasis in CRC cells. Translation-reporter system and polysome profiling assays further showed that KLF16 can effectively promote cap-independent translation of ATF4, which can enhance ER-phagy and proliferation of CRC cells. Overall, our study unveils a previously unrecognized role for KLF16 as an ER stress regulator through mediating translational reprogramming to enhance stress tolerance of CRC cells and provides a potential therapeutic vulnerability.

Keywords: ER stress; carcinogenesis; nucleolar homeostasis; stress tolerance; translational reprogramming

DOI: https://doi.org/10.1016/j.ymthe.2022.04.022