The Maternal Embryonic Leucine Zipper Kinase, or MELK, gene contains the instructional code for producing the MELK protein. This protein is a member of the serine/threonine kinase family, enzymes that add phosphate groups to specific proteins to alter their activity, a process that regulates many cellular activities. Its expression was first identified in the developing eggs and early embryos of mice, pointing to its involvement in basic biological events. The protein is highly conserved across many species, indicating its role in established cellular pathways.
The Normal Function of the MELK Gene
The MELK protein is a regulator of the cell cycle, the orderly sequence of events by which a cell duplicates its contents and divides. It helps ensure the fidelity of mitosis, the phase where duplicated chromosomes are separated into two new nuclei. Its activity levels peak during this mitotic phase, where it phosphorylates other proteins like CDC25B. This action directs the cellular machinery to ensure cell division proceeds correctly.
This gene’s function is pronounced during embryonic development, where rapid cell proliferation is necessary to form complex tissues and organs. The presence of MELK mRNA in unfertilized eggs and early-stage embryos confirms its role in the earliest stages of life. It is also involved in maintaining stem cells, the body’s internal repair system. The gene helps preserve the self-renewal capacity of these undifferentiated cells, including neural progenitors necessary for brain development.
The MELK protein also participates in apoptosis, or programmed cell death, a process for removing old or damaged cells. Its role in apoptosis is complex, as some studies show it can promote this process by activating other proteins like MAP3K5/ASK1. This dual function in both promoting cell division and participating in cell death demonstrates its role in maintaining a healthy balance within tissues, ensuring new cells are made as old ones are eliminated.
Association with Cancer
The connection between the MELK gene and cancer is one of overexpression. In many cancers, the gene is far more active than in healthy tissues, leading to an overabundance of the MELK protein. High MELK expression has been documented in cancers of the breast, brain, prostate, and lung. It is often elevated in aggressive subtypes, such as triple-negative breast cancer and glioblastoma, the most aggressive form of brain cancer.
This overexpression is strongly associated with negative patient outcomes. Higher levels of MELK correlate with more advanced tumor stages, increased likelihood of recurrence, and poorer prognosis. In neuroblastoma, a cancer affecting young children, high MELK expression is linked to high-risk disease and lower survival rates. Elevated MELK levels can also predict resistance to treatments like radiation, particularly in breast cancer.
The surplus of MELK protein is thought to fuel cancer progression by disrupting the normal checks and balances of cell division, promoting uncontrolled proliferation. It can also interfere with apoptosis, allowing malignant cells to evade programmed cell death. In some cancer stem cells, MELK interacts with oncogenic transcription factors like c-Jun and FoxM1, an interaction not observed in normal stem cells. This suggests MELK’s function is co-opted by cancer cells to support their survival and expansion.
Therapeutic Targeting of MELK
Given the link between MELK overexpression and cancer growth, scientists have identified it as a target for new therapies. The strategy revolves around developing drugs, known as MELK inhibitors, that specifically block the MELK protein’s function. These drugs are designed to fit into the active site of the enzyme, preventing its phosphorylation function. This disrupts the signaling pathways that cancer cells rely on for survival, aiming to halt tumor growth while sparing healthy cells.
One of the most studied MELK inhibitors is the compound OTSSP167. Preclinical studies show this inhibitor suppresses the growth of various cancers, including breast, lung, and prostate. In neuroblastoma research, OTSSP167 suppressed tumor growth and prolonged survival in a model of minimal residual disease. The effectiveness of such inhibitors often correlates with the level of MELK expression, meaning tumors with the highest levels are the most sensitive.
This approach has advanced to clinical trials, with inhibitors like OTSSP167 being evaluated in humans for diseases like advanced breast cancer. These trials aim to determine the drug’s safety, tolerability, and appropriate dosage. MELK inhibitors represent a targeted strategy for aggressive cancers with limited treatment options. This may also make tumors more sensitive to other treatments like radiation or chemotherapy.
Ongoing Scientific Debate
While the link between MELK and cancer is well-documented, its precise role remains a subject of scientific debate. The controversy is whether the MELK gene is a driver of cancer, required for cancer cells to survive, or if its high expression is a byproduct of rapid cell division. Initial evidence for its role came from studies using RNA interference (RNAi) to reduce MELK levels, which impaired the growth of various cancer cell lines.
This view was challenged by research using the precise gene-editing tool CRISPR/Cas9. In a 2017 study, researchers used CRISPR to completely remove the MELK gene from several cancer cell lines, including triple-negative breast cancer cells. They reported that eliminating MELK had no effect on the cells’ ability to divide and grow. This finding suggested that MELK might not be the cancer dependency it was thought to be.
The discrepancy between the RNAi and CRISPR results has fueled an ongoing debate. One hypothesis is that the effects in the RNAi studies were due to “off-target” effects, where the technique inadvertently affected other genes. Conversely, some argue that cancer cells may adapt to the complete loss of the MELK gene via CRISPR, while remaining vulnerable to its sudden inhibition by a drug. This debate highlights the complexities of cancer biology and how new technologies can challenge established findings.