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

Pariyakorn Udomwan,Sittiruk Roytrakul,Nuchsupha Sunthamala,Supawadee Suebsasana,Panwad Tongchai,Chamsai Pientong,Ati Burassakarn,Tipaya Ekalaksananan

doi:10.3390/ijms22136806

Abstract

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.

Highlights

High-risk human papillomaviruses are one of the human papillomavirus subsets that can efficiently promote infected-keratinocytes’ transformation to cancers, and they are identified as an etiology of cervical, anogenital, and head and neck cancers [1]
The overexpression of early protein 6 (E6) and E7 mainly depends on the availability of host-transcription factors [4], e.g., activator protein-1 (AP-1), nuclear factor 1 (NF1), and specificity protein 1 (SP1), that have been reported to activate on the promotor (p97) region of the E6/E7 gene [5]
Evasion of apoptosis is a hallmark of HPV-associated cervical cancer, and causes ineffective management in patients being treated according to conventional therapeutic strategies [45,46,47]

Summary

Introduction

High-risk human papillomaviruses (hr-HPVs) are one of the human papillomavirus subsets that can efficiently promote infected-keratinocytes’ transformation to cancers, and they are identified as an etiology of cervical, anogenital, and head and neck cancers [1]. The infection of hr-HPVs signifies a major health problem for the world population, accounting for 5% of cancers globally and affecting 99% of cervical cancers [2]. The intracellular accumulation of two major viral oncoproteins, E6 and E7, plays a functional role in the HPV-induced keratinocyte transformation [3]. The E6 oncoprotein potently inhibits several signalings of tumor suppressor pathways, those concerning the p53 cascades, which are important for tumor initiation and cancer maintenance [7]

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