Proliferation and Apoptosis Pathways and Factors in Oral Squamous Cell Carcinoma

Abstract

Oral cancer is the most common form of head and neck squamous cell carcinoma (HNSCC) and most frequently presents as oral squamous cell carcinoma (OSCC), which is associated with an alarmingly high mortality rate. Internationally, a plethora of research to further our understanding of the molecular pathways related to oral cancer is performed. This research is of value for early diagnosis, prognosis, and the investigation of new drugs that can ameliorate the harmful effects of oral cancer and provide optimal patient outcomes with minimal long-term complications. Two pathways on which the progression of OSCC depends on are those of proliferation and apoptosis, which overlap at many junctions. Herein, we aim to review these pathways and factors related to OSCC progression. Publicly available search engines, PubMed and Google Scholar, were used with the following keywords to identify relevant literature: oral cancer, proliferation, proliferation factors, genes, mutations, and tumor suppressor. We anticipate that the use of information provided through this review will further progress translational cancer research work in the field of oral cancer.

Keywords: apoptosis; apoptotic factors; oral cancer; proliferation; proliferation factors; tumor suppressor.

Figure 1

Schematic representation of common proliferative signalling pathways. An overview of proliferative signal transduction through classical Ras-Raf-MEK-ERK/MAPK and PI3K-AKT-mTOR pathways is presented here. Receptor tyrosine kinases (RTKs) such as epidermal growth factor (EGRF) dimerise upon ligand activation (such as through EGF) and recruit proteins containing Src homology (SH) 2 domains such as GRB2 and SHC [32]. In the Raf axis, son of sevenless (SOS) activates Ras through guanine triphosphate (GTP) exchange [33], which subsequently recruits Raf to the plasma membrane where it becomes activated [34]. Raf initiates a signalling cascade by phosphorylating MEK1/2, which in turn phosphorylates ERK (also known as mitogen activated kinase; MAPK) [35]. ERK/MAPK translocates to the nucleus where it activates transcription factors (e.g., c-MYC, c-JUN, and c-FOS), which increase the transcription of cyclin D mRNA [36]. In the AKT axis, RTK dimerization activates PI3K, which stimulates the production of phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP3 production recruits AKT to the plasma membrane where phosphorylation events by PDK1 and mechanistic target of rapamycin complex (mTORC) 2 result in its activation [37,38]. AKT is able to activate mTORC1 and inhibit the action of TSC2, which is a negative regulator of mTORC 1. mTORC1 inhibits 4E-BP, which is a negative regulator of translation [39]. These events result in the production of cyclin D, which complexes with cyclin dependent kinases (CDKs) 4 and 6 to inhibit retinoblastoma (RB) protein and allow E2F transcription factors to produce cyclin E [40,41]. Cyclin E production drives the cell through the G₁/S transition of the cell cycle towards G₂ and mitosis [42].

Figure 2

Schematic representation of the cell cycle. Reversibly quiescent cells (G₀) are able to re-enter the cell cycle and begin cycling in Gap 1 (G₁) phase upon receiving proper mitogenic signalling. This causes the upregulation of D-type cyclin production which complex with cyclin dependent kinases (CDKs) 4 and 6 and partially inactivates retinoblastoma protein (RB) [42]. This allows for the production of E-type cyclins that interact with CDK2 to hyper-phosphorylate and fully inactivate RB. This inactivation results in the expression of E2F family transcription factors which upregulate the expression of DNA replication proteins, such as DNA polymerase in preparation for Synthesis (S) phase [40]. In the event of DNA damage, sensor kinases ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad-3 related (ATR) phosphorylate p53 and the checkpoint kinases Chk1 and Chk2 which collectively signal effectors such as cyclin-dependent kinase inhibitors (CKIs) that arrest the cell at G₁/S to allow for DNA repair or, otherwise, initiation of apoptosis [83]. A-type cyclins are produced in late S phase and drive mitosis onset, followed by their degradation and production of B-type cyclins that complex with CDK1 and predominantly drive the cell through Mitosis (M) phase [42].

Figure 3

Schematic representation of canonical apoptotic pathways. In the intrinsic pathway, pro-apoptotic BH3-only proteins act as sensors and interact with anti-apoptotic Bcl-2 proteins upon activation by stress signals. Activation over a critical threshold overcomes the anti-apoptotic effects of Bcl-2 proteins and promotes oligomerization of Bax/Bak channels in the mitochondrial membrane that permit the release of the intermembrane space protein cytochrome C [104]. Cytoplasmic cytochrome C promotes apoptosome formation (complex of Apaf1, caspase 9, and cytochrome C) which activates caspases 3 and 7. This results in a signalling cascade providing activation of additional caspase family members which proceed to act on a wide range of cellular targets, ultimately resulting in cell death [105,106]. In the extrinsic pathway, activation of death receptors (e.g., Fas, tumour necrosis factor receptor 1; TNFR1) by cognate ligands (e.g., Fas ligand;FasL, tumour necrosis factor alpha; TNF-α) recruits Fas-associated protein with death domain (FADD) adaptor proteins and procaspase 8 to form the death-inducing signalling complex (DISC) [107]. Procaspase 8 molecules aggregate resulting in autoprocessing and subsequent activation. Active caspase 8 activates caspase 3 and Bid (in its active truncated form; tBid) and converges with the intrinsic pathway via mitochondrial Bax-Bak channel formation [108]. In the granzyme B pathway, granules containing granzyme B and perforin are released from immune cells such as cytotoxic T lymphocytes and natural killer (NK) cells. Perforin oligomerises in the target cell membrane, allowing for entry of granzyme B which is also capable then of activating caspase 3 and Bid, similar to caspase 8 [109].