Connexin 36 Mediated Intercellular Endoplasmic Reticulum Stress Transmission Induces SSTA Resistance in Growth Hormone Pituitary Adenoma

Wang, Zihan; Lei, Zhuowei; Wang, Quanji; Jiang, Qian; Zhang, Zhuo; Liu, Xiaojin; Xing, Biao; Li, Sihan; Guo, Xiang; Liu, Yanchao; Li, Xingbo; Qi, Yiwei; Shu, Kai; Zhang, Huaqiu; Huang, Yimin; Lei, Ting

doi:10.7150/ijbs.86736

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Int J Biol Sci 2024; 20(2):801-817. doi:10.7150/ijbs.86736 This issue Cite

Research Paper

Connexin 36 Mediated Intercellular Endoplasmic Reticulum Stress Transmission Induces SSTA Resistance in Growth Hormone Pituitary Adenoma

Zihan Wang^1,2,3#, Zhuowei Lei^4#, Quanji Wang^1,2,3, Qian Jiang^1,2,3, Zhuo Zhang^1,2,3, Xiaojin Liu^1,2,3, Biao Xing^1,2,3, Sihan Li^1,2,3, Xiang Guo^1,2,3, Yanchao Liu^1,2,3, Xingbo Li^1,2,3, Yiwei Qi^1,2,3, Kai Shu^1,2,3, Huaqiu Zhang^1,2,3, Yimin Huang^1,2,3*✉, Ting Lei^1,2,3*✉

1. Department of Neurosurgery, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China.
2. Sino-German Neuro-Oncology Molecular Laboratory, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China.
3. Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, 430030, China.
4. Department of Orthopedics, Tongji hospital of Tongji medical college of Huazhong University of Science and Technology, Wuhan, 430030, China.
# Equal Contribution.
* Equal Contribution.

Citation:

Wang Z, Lei Z, Wang Q, Jiang Q, Zhang Z, Liu X, Xing B, Li S, Guo X, Liu Y, Li X, Qi Y, Shu K, Zhang H, Huang Y, Lei T. Connexin 36 Mediated Intercellular Endoplasmic Reticulum Stress Transmission Induces SSTA Resistance in Growth Hormone Pituitary Adenoma. Int J Biol Sci 2024; 20(2):801-817. doi:10.7150/ijbs.86736. https://www.ijbs.com/v20p0801.htm

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Abstract

Somatostatin analogues (SSTA) are first-line pharmacological treatment choice for acromegaly, which received satisfying tumor shrinkage and normalization of growth hormone. However, there are still patients unresponsive to SSTA, and the underline mechanism remains unknown. Besides, there is no evidence regarding the role of endoplasmic reticulum stress (ERS) and its transmission in SSTA resistance, which also require investigation. Primary growth hormone adenoma cells and cell lines were treated with SSTA; autophagy double-labeled LC3 (mRFP-GFP) adenovirus transfection, flow cytometry sorting, western blotting, calcium imaging as well as immunofluorescence staining were used to determine ERS and autophagy signal transmission; xenograft and syngeneic tumor in vivo model were exploited to confirm the ERS signal transmission mediated effect. Our results revealed that SSTA induces ERS in pituitary growth hormone (GH) adenoma cells. The ERS signals can be intercellularly transmitted, leading to less responsible to SSTA treatment. Moreover, SSTA stimulates inositol triphosphate (IP₃) elevation, mediating ERS intercellular transfer. In addition, connexin 36 tunnels ERS transmission, and its blocker, Quinine, exhibits a synergistic effect with SSTA treating GH adenoma. Our study provided insight into ERS intercellular transmission mediated SSTA resistance, which could be translated into clinical usage to improve SSTA efficiency in GH adenoma treatment.

Keywords: Growth hormone-secreting pituitary adenoma, Somatostatin, Endoplasmic reticulum stress, Connexin 36, Gap junctions, Quinine

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APA

Wang, Z., Lei, Z., Wang, Q., Jiang, Q., Zhang, Z., Liu, X., Xing, B., Li, S., Guo, X., Liu, Y., Li, X., Qi, Y., Shu, K., Zhang, H., Huang, Y., Lei, T. (2024). Connexin 36 Mediated Intercellular Endoplasmic Reticulum Stress Transmission Induces SSTA Resistance in Growth Hormone Pituitary Adenoma. International Journal of Biological Sciences, 20(2), 801-817. https://doi.org/10.7150/ijbs.86736.

ACS

Wang, Z.; Lei, Z.; Wang, Q.; Jiang, Q.; Zhang, Z.; Liu, X.; Xing, B.; Li, S.; Guo, X.; Liu, Y.; Li, X.; Qi, Y.; Shu, K.; Zhang, H.; Huang, Y.; Lei, T. Connexin 36 Mediated Intercellular Endoplasmic Reticulum Stress Transmission Induces SSTA Resistance in Growth Hormone Pituitary Adenoma. Int. J. Biol. Sci. 2024, 20 (2), 801-817. DOI: 10.7150/ijbs.86736.

NLM

CSE

Wang Z, Lei Z, Wang Q, Jiang Q, Zhang Z, Liu X, Xing B, Li S, Guo X, Liu Y, Li X, Qi Y, Shu K, Zhang H, Huang Y, Lei T. 2024. Connexin 36 Mediated Intercellular Endoplasmic Reticulum Stress Transmission Induces SSTA Resistance in Growth Hormone Pituitary Adenoma. Int J Biol Sci. 20(2):801-817.

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