Proteomics Analysis of Andrographolide-Induced Apoptosis via the Regulation of Tumor Suppressor p53 Proteolysis in Cervical Cancer-Derived Human Papillomavirus 16-Positive Cell Lines

• Published in: International journal of molecular sciences Vol. 22; no. 13; p. 6806
• Main Authors: Udomwan, Pariyakorn, Pientong, Chamsai, Tongchai, Panwad, Burassakarn, Ati, Sunthamala, Nuchsupha, Roytrakul, Sittiruk, Suebsasana, Supawadee, Ekalaksananan, Tipaya
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.07.2021; MDPI
• Subjects: andrographolide (Androg); Apoptosis; Cancer therapies; Carcinogenesis; Carcinogens; Cell cycle; Cell death; Cervical cancer; Cervix; Cytotoxicity; Etiology; Genomes; Hepatitis; Herbal medicine; Human papillomavirus; human papillomaviruses (HPVs); Infections; p53 Protein; Papillomaviridae; Proteins; Proteolysis; Proteomics; Signal transduction; Tumor cell lines; Tumor suppressor genes; tumor suppressor protein p53 (p53); Ubiquitin; Ubiquitin-protein ligase; Viruses
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22136806

Regardless of the prophylactic vaccine accessibility, persistent infections of high-risk human papillomaviruses (hr-HPVs), recognized as an etiology of cervical cancers, continues to represent a major health problem for the world population. An overexpression of viral early protein 6 (E6) is linked to carcinogenesis. E6 induces anti-apoptosis by degrading tumor suppressor proteins p53 (p53) via E6-E6-associated protein (E6AP)-mediated polyubiquitination. Thus, the restoration of apoptosis by interfering with the E6 function has been proposed as a selective medicinal strategy. This study aimed to determine the activities of andrographolide (Androg) on the disturbance of E6-mediated p53 degradation in cervical cancer cell lines using a proteomic approach. These results demonstrated that Androg could restore the intracellular p53 level, leading to apoptosis-induced cell death in HPV16-positive cervical cancer cell lines, SiHa and CaSki. Mechanistically, the anti-tumor activity of Androg essentially relied on the reduction in host cell proteins, which are associated with ubiquitin-mediated proteolysis pathways, particularly HERC4 and SMURF2. They are gradually suppressed in Androg-treated HPV16-positive cervical cancer cells. Collectively, the restoration of p53 in HPV16-positive cervical cancer cells might be achieved by disruption of E3 ubiquitin ligase activity by Androg, which could be an alternative treatment for HPV-associated epithelial lesions.