The clinical scenario of acquired cisplatin resistance is considered as a major impediment in cervical cancer treatment. Bulky drug-DNA adducts formed by cisplatin elicits DNA damage response (DDR) which either subsequently induces apoptosis in the cervical cancer cells or enables them to adapt with drug assault by invigorating pro-survival molecular cascades. When HPV infected cervical cancer cells encounter cisplatin, a complex molecular interaction between deregulated tumor suppressors, DNA damage-repair enzymes, and prosurvival molecules get initiated. Ambiguous molecular triggers allow cancer cells to cull apoptosis by opting for a survival fate. Overriding of the apoptotic cues by the pro-survival cues renders a cisplatin resistant phenotype in the tumor microenvironment. The present review undrapes the impact of deregulated signaling nexus formed due to crosstalk of the key molecules related to cell survival and apoptosis in orchestrating platinum resistance in cervical cancer.
- Cervical cancer
- Cisplatin resistance
- tumor suppressors
- DNA-damage repair
- prosurvival signaling
Cervical cancer, one of the widespread gynecological cancers, accounts for the maximum deaths amongst women across the globe. As per GLOBOCAN 2018, cervical cancer is helmed as the fourth leading cause of mortality and morbidity in women after breast and ovarian cancers . As revealed from the data collated by World Health Organization (WHO) in 2013, over 85% of the cervical cancer cases had surfaced mostly from developing countries with a poor socio-economic backdrop . Women, owing to lack of awareness, often arrive for seeking medical help when the malignant growth of cervix has attained advancement .
Infections with a special class of oncogenic DNA viruses called
Cervical cancer progresses through stages of
In the process of HPV mediated cervical carcinogenesis several molecular changes are incited which remodels the metabolic profiles of the cervix . HPV induced metabolic paradigm shift bestows the cells with therapy evasive properties. Consequentially, neoplastic cells emerge as highly dynamic and evolving entities . On encountering drugs, the rewired signaling cascades of the tumor cells residing in the cervix get triggered. These eventuate in increased metabolism of chemotherapeutics like cisplatin, finally catering in reduced intracellular drug accumulation , paving a way for acquired cisplatin resistance. This chapter majorly discusses the mechanisms underlying the acquirement of resistance towards cisplatin as a result of deregulated activities of tumor suppressors, DNA damage repair enzymes and prosurvival molecules, mediated due to HPV infections.
2. HPVs: Integral to etiology of cervical cancer
HPVs are relatively small non-enveloped viruses with a diameter of 55 nm. It has a double stranded circular DNA genome which is 8 kb long and is enclosed within an
These miniscule infectious agents access the cervical epithelial layer through crevices or microabrasions that generally forms due to mechanical shock or injury. Following entry, HPVs integrate their genome with that of the host to initiate the process of malignant transformation of the cervix (Figure 1). The carcinogenesis of cervical epithelium begins with the onset of viral lifecycle which initiates with viral entry into basal cell layer of the epithelium . The basal cell layer of the cervical epidermis enables multiplication and replication of the virus by providing them with a suitable microenvironment. Molecules expressed by the basal cells such as
3. Concomitant molecular changes during cervical carcinogenesis upon HPV infection: an escape route to cisplatin therapy
3.1 Onslaught of HPVs deregulates tumor suppressors
HPV mediated neoplastic transformation of cervix kick starts with the abridgement of tumor suppressor functions. An array of experimentations conducted in
3.2 Cisplatin insensitivity: a consequence of HPV driven deregulation of tumor suppressors
HPV immortalized cervical cancer cells, especially those at the invasive stages, are subjected to treatment with platinum-ligated drugs like cisplatin. Following its cellular entry, cisplatin transforms into a very strong electrophilic species by hydrolytic activation. Such an activated drug generates an electrophilic attack on cellular nucleophiles like DNA and results in formation of bulky drug-DNA adducts which are beyond repair . Inevitably, cancer cells harboring complex cisplatin modified DNA will be arrested in the G1 phase of the cell cycle particularly; due to generation of DDR response and subsequent activation of p53. Generation of cisplatin-DNA adducts activates
In HPV infected cells, this entire p53 dictated cell-death inducing pathway is compromised owing to functional absence of the tumor suppressors. E6 mediated prior degradation of p53 in cervical cancer cells, unprecedentedly makes them tolerant to the drug. It has been experimentally demonstrated that p53-Bax signaling axis elicited cisplatin induced apoptosis in cervical cancer cells . Even in multiple clinical studies, patients retaining wild-type p53 have been found to respond better to platinum based chemotherapy . Expression patterns of p53 are predictive of success rate of cisplatin treatment in adeno-carcinoma of the uterine cervix . A very recent report has envisaged the contribution of p53 in restoring cisplatin sensitivity in CDDP resistant cervical cancer cells, particularly during combination treatment with doxorubicin .
3.3 HPV mediated impairment of DNA repair machinery: an auto-corrector of cisplatin-DNA adducts in cervical cancer
Early genes E1 and E2 drive the process of viral replication in the host by acting as an
The host cell has various repair pathways working in a well-knitted fashion to clear off irrelevant mistakes that may arise during the process of DNA replication. Some of these include-
Cervical cancer cells infected with hr-HPVs exhibit an upregulation of
In addition to ATM, HPVs also activate ATR pathway. In HPV infected cells considerably higher levels of
3.4 HPV seized DNA repair machineries of cervical cancer cells encourages acquired Cisplatin resistance
Upregulated activities of DNA damage repair enzymes empower cervical cancer cells to quickly repair the cisplatin-DNA adducts. Cisplatin generates intrastrand cross-links in the DNA to primarily activate
3.5 HPV mediated upregulation of prosurvival signaling cascades: Another contributor of cisplatin resistance in cervical cancer
3.5.1 Activation of PI3K/Akt signaling
PI3K, particularly was found to be amplified and overtly activated in HPV-induced cervical cancers [87, 88]. The activation of MAPK/ERK in turn alters transcription of multiple genes that are important for regulation of cell-cycle progression and cell proliferation. Thus, activation of PI3K begets in Akt activation via phosphorylation of the protein in most of the HPV infected cancers. HPV16 E6 activates receptor protein tyrosine kinases (RTKs) viz. epidermal growth factor receptor (EGFR), insulin receptor beta and insulin-like growth factor receptor beta; lying upstream of the PI3K/Akt pathway . Activation of Akt results into a series of changes in downstream targets. Akt, furthermore can phosphorylate E6 to promote its ability to interact with 14–3-3σ, an important protein required for carcinogenic progression . A strong association between HPV and surged c-myc expression has been evidenced [91, 92, 93]. Reportedly, interaction between E6 and c-myc activates the enzymatic function of
3.5.2 Activation of mTOR signaling
mTOR kinase functions as a cellular rheostat that amalgamates cellular signaling pathways after sensing growth factor, starvation and energy status. Recently, it has been reported that Akt/mTOR activation occurs immediately after exposure to HPV16 pseudovirions . mTOR activation is frequently observed in cervical squamous cell carcinoma, as well as in most HPV positive head and neck squamous cell carcinomas (HNSCC), and oropharyngeal cancers (OPSCC) [93, 97]. HPV oncoproteins E7 and E6 can chronologically activate AKT through pRb binding and subsequently stimulate mTOR in its complex 1 (mTORC1). These upregulated prosurvival signaling molecules lead to a shift in metabolic paradigm of the cancer cells. When subjected to cisplatin treatment, the HPV infected cervical cancer cells start to metabolize the drug faster than usual. This result in rapid drug efflux and eventually lessens intracellular cisplatin levels to orchestrate cisplatin resistance. Therefore, most cisplatin resistant cervical cancer cells are often characterized by the presence of greater levels of cisplatin efflux pumps [98, 99]. Of late, Li et al. showed in their study that in cisplatin resistant cervical cancer cells with upregulated PI3K/Akt pathway, espouses surged levels of
3.5.3 Activation of the Wnt pathway
Nuclear accumulation of β-catenin due to activation of the canonical Wnt/β-Catenin pathway leads to transcriptional activation of a plethora of proliferative genes. This is highly characteristic to HPV16-positive invasive cancers as well as early dysplastic lesions [102, 103]. This phenomenon of nuclear accumulation of β-catenin positively correlates with progression of cervical cancer . Accordingly, β-catenin was found in higher frequencies within the nucleus of cervical cancer cell line SiHa (bearing integrated HPV16) and HeLa (bearing integrated HPV18) . Lichtig et al. proposed that HPV16 E6 could mechanistically activate Wnt/β-catenin pathway in a p53 independent fashion . β-catenin signaling pathway exhibited a regulatory activity over acquired resistance to cisplatin via upregulation of Bcl-xl . Cisplatin resistance got promoted in neoplasia due to shut down of GSK-3β owing to activation of Wnt/β-catenin signaling .
3.5.4 Activation of the Notch pathway
Cellular prosurvival juxtracrine signaling axis involving TGFβ/Notch1 is found to be exhilarated in invasive cervical cancer . As the cervical lesions progressed from intraepithelial lesions III to microinvasive carcinoma, Notch1 translocated from the cytoplasm to the nucleus for ease of function . HPV E6 has been identified as an activator of Notch protein in multiple cervical cancer cell lines . Upregulated activities of notch protein induce stemness in cervical cancer cells, thereby enabling them to evade cisplatin driven cytotoxicity. Inhibition of Notch1was found to revert epithelial to mesenchymal transition (EMT); restoring cisplatin sensitivity .
3.5.5 Telomerase activation
Orchestration of HPV induced signaling nexus in promoting cisplatin resistance in cervical cancer is well depicted in Figure 2.
4. Perspective insights
As the virus hijacks the host system, it flips the molecular dynamics according to its own survival benefit. As discussed in this review, loss of function of tumor suppressors, magnified activities of DNA repair enzymes and constitutional activation prosurvival signaling cascades in the HPV infected cervix, make the situation precarious. The conundrum of drug resistance that arises as a result of these existent changes, stymies therapy. Tracking these prior change can aid in planning conventional therapeutic regimes. Thus, these molecules can act as valuable prognostic biomarker before administration of cisplatin based chemotherapy to cervical cancer patients.
The authors are indebted to the Director, Chittaranjan National Cancer Institute, Kolkata for encouraging the idea of the manuscript. The authors are grateful to Ministry of Health & Family Welfare, Govt of India for financial support to undertake the research.
Conflict of interest
Authors declare no conflict of interest.
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