Selective degradation of PL2L60 by metabolic stresses‑induced autophagy suppresses multi‑cancer growth

Sun,Lei; Hui,Fu; Tang,Gao-Yan; Shen,Hai-Lian; Cao,Xue-Lei; Gao,Jian-Xin; Li,Lin-Feng

doi:10.3892/or.2024.8700

Selective degradation of PL2L60 by metabolic stresses‑induced autophagy suppresses multi‑cancer growth

Authors:
- Lei Sun
- Fu Hui
- Gao-Yan Tang
- Hai-Lian Shen
- Xue-Lei Cao
- Jian-Xin Gao
- Lin-Feng Li
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Affiliations: The State Key Laboratory of Oncogenes and Related Genes, and The Laboratory of Tumorigenesis and Immunity, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, PuDong, Shanghai 200127, P.R. China, Department of Oncology, First Affiliated Hospital of Weifang Medical University, Weifang, Shandong 261000, P.R. China, Sam and Ann Barshop Institute for Longevity of Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78292, USA, Department of Clinical Laboratory, Qi Lu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China
Published online on: January 12, 2024 https://doi.org/10.3892/or.2024.8700
Article Number: 41
Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

It has been reported that PL2L60 proteins, a product of PIWIL2 gene which might be activated by an intragenic promoter, could mediate a common pathway specifically for tumorigenesis. In the present study, it was further identified by using western blot assay that the PL2L60 proteins could be degraded in cancer cells through a mechanism of selective autophagy in response to oxidative stress. The PL2L60 was downregulated in various types of cancer cells under the hypoxic condition independently of HIF‑1α, resulting in apoptosis of cancer cells. Inhibition of autophagy by small interfering RNA targeting of either Beclin‑1 (BECN1) or Atg5 resulted in restoration of PL2L60 expression in hypoxic cancer cell. The hypoxic degradation of PL2L60 was also blocked by the attenuation of the autophagosome membrane protein Atg8/microtubule‑associated protein 1 light chain 3 (LC3) or autophagy cargo protein p62 expression. Surprisingly, Immunofluorescence analysis demonstrated that LC3 could be directly bound to PL2L60 and was required for the transport of PL2L60 from the nucleus to the cytoplasm for lysosomal flux under basal or activated autophagy in cancer cells. Moreover, flow cytometric analysis displayed that knocking down of PL2L60 mRNA but not PIWIL2 mRNA effectively inhibited cancer cell proliferation and promoted apoptosis of cancer cells. The similar results were obtained from in vivo tumorigenic experiment, in which PL2L60 downregulation in necroptosis areas was confirmed by immunohistochemistry. These results suggested that various cancer could be suppressed by promoting autophagy. The present study revealed a key role of autophagic degradation of PL2L60 in hypoxia‑induced cancer cell death, which could be used as a novel therapeutic target of cancer.

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