A cancer cell does not simply die. It survives, divides, spreads, and ignores the death signals that should come from the body itself. This is what makes tongue squamous cell carcinoma one of the most aggressive malignancies in the head and neck region. However, a study from the Department of Oral Medicine, Faculty of Dentistry, Universitas Gadjah Mada, has uncovered a small opening that could potentially change the way we fight it.
Prof. drg. Supriatno, M.Kes, MDSc, PhD, a researcher and lecturer at the Faculty of Dentistry, Universitas Gadjah Mada, found that a protein called Jab1 plays a key role in the survival of tongue cancer cells. More importantly, when the expression of this protein was suppressed using an antisense approach, the cancer cells instead turned against themselves and underwent programmed cell death.
When the Cell-Cycle Guardian Is Removed
To understand this finding, it is necessary to become acquainted with two key players: Jab1 and p27 Kip1.
Jab1, or Jun activation domain-binding protein 1, is a protein that functions somewhat like a “clean-up crew” inside the cell. One of its roles is to degrade p27 Kip1, a protein that naturally acts as a brake on the cell cycle. When p27 Kip1 is active, it prevents cells from dividing uncontrollably. However, when Jab1 becomes overly dominant, p27 Kip1 is destroyed before it can perform its function. The cell consequently loses its brake, continues dividing uncontrollably, and cancer develops.
In many human cancers, including head and neck carcinoma, low levels of p27 Kip1 have long been associated with poor prognosis. This inverse relationship between high Jab1 expression and low p27 Kip1 expression became the starting point for Supriatno's research.
Sp-C1 Cells and the Antisense Strategy
In this study, Supriatno used a human tongue cancer cell line called Supri’s clone-1, or Sp-C1, which was developed in his own laboratory. The name is no coincidence: Sp-C1 is a cell line developed by the same researcher, making it one of the Faculty of Dentistry, Universitas Gadjah Mada's original contributions to oral oncology research.
The strategy employed was an antisense oligonucleotide, a kind of “molecular feedback mechanism” designed to specifically block Jab1 gene expression. The antisense oligonucleotide was introduced into Sp-C1 cells, after which the researchers observed what happened.
The results were compelling. Flow cytometry analysis showed that cells treated with Jab1 antisense experienced an increase in early apoptosis to 33.5%, considerably higher than the 18.8% observed in control cells. Late apoptosis reached 17.6%. The cells did not merely stop growing. They underwent programmed cell death.
Caspases as Cellular Executioners
This orderly cell death did not occur randomly. Behind it was a precise biochemical mechanism involving enzymes known as caspases.
The study measured the activity of two key caspases: caspase-3 and caspase-9. Both are major components of the apoptotic pathway, particularly the extrinsic and intrinsic pathways. The results showed a 2.4-fold increase in caspase-3 proteolytic activity and a 1.9-fold increase in caspase-9 activity in antisense-treated cells compared with control cells.
“Down-regulation of Jab1 by the antisense approach could be a useful apoptosis-modulating strategy for treatment of head and neck cancers.”
Supriatno wrote this statement in his paper, published in the January–March 2011 issue of the Indonesian Journal of Cancer. The statement is simple, but its implications are substantial: if Jab1 can be targeted therapeutically, it could provide a new pathway to explore in the fight against head and neck cancers, particularly cancers that have become resistant to conventional treatments.
New Hope at the Edge of the Tongue
Tongue squamous cell carcinoma is known for its high rate of local recurrence following initial treatment. Even with all the advances in medicine, the mortality-to-incidence ratio for this cancer has changed little over the past decade. This is not merely a statistic. It represents thousands of patients who survive surgery and radiotherapy only to discover that their tumors have returned.
Supriatno's research does not immediately offer a new treatment. Nor does it claim to do so. Instead, it offers a deeper understanding of the molecular mechanisms underlying cancer cell survival, along with a strategy that has been shown in vitro to reverse the process: suppress Jab1, release p27 Kip1, and allow cancer cells to undergo their natural programmed death.
Of course, the path from the laboratory bench to the patient's bedside is still a long one. Further research is needed to determine whether the same approach applies to other types of tumors and how antisense molecules can be safely delivered into the human body. Yet every therapy available today once began with a question in a laboratory—and with a single cell that eventually agreed to die.
Source DOI: https://doi.org/10.33371/ijoc.v5i1.88
Authors: Anny Anggraini; drg. Achmad Zam Zam Aghasy, M.Kes.
Photo: Freepik