Journal of Tumour Research & Reports

Apoptotic Pathways Activated by Oncogenes: Implications for Cancer Therapy

Mary Viola^* Department of Cancer, Dalhousie University, Nova Scotia, Canada
^*Correspondence: Mary Viola, Department of Cancer, Dalhousie University, Nova Scotia, Canada, Email:

Received: 03-Jun-2024, Manuscript No. JTRR-24-25914; Editor assigned: 05-Jun-2024, Pre QC No. JTRR-24-25914 (PQ); Reviewed: 19-Jun-2024, QC No. JTRR-24-25914; Revised: 26-Jun-2024, Manuscript No. JTRR-24-25914 (R); Published: 03-Jul-2024, DOI: 10.35248/2684-1614.24.9.225

Description

Cancer is fundamentally a disease of dysregulated cell growth and survival, driven by genetic mutations and alterations in cellular signaling pathways. Among these genetic changes, oncogenes play a potential role in initiating and promoting tumorigenesis. Oncogenes are mutated or overexpressed versions of normal cellular genes (proto-oncogenes) that, when activated, can drive uncontrolled cell proliferation. However, paradoxically, these oncogenes can also induce apoptosis, a form of programmed cell death.

Mechanisms of oncogene-induced apoptosis

Oncogene-Induced Apoptosis (OIA) occurs as a cellular defense mechanism to prevent the uncontrolled growth of potentially malignant cells. Several key oncogenes, including Myc, Ras, and E2F1, have been shown to trigger apoptotic pathways under certain conditions. The mechanisms through which these oncogenes induce apoptosis involve complex signaling networks that balance cell survival and death.

Myc-induced apoptosis: Myc is a transcription factor that regulates the expression of numerous genes involved in cell proliferation, metabolism, and apoptosis. While Myc activation promotes cell growth, excessive Myc expression can lead to apoptosis. This is mediated through several pathways such as ARF-p53 pathway and Bim and Bcl-2 family proteins. Myc upregulates ARF, a tumor suppressor that inhibits MDM2, leading to the stabilization and activation of p53. Activated p53 induces the expression of pro-apoptotic genes such as Bax, PUMA, and NOXA, leading to Mitochondrial Outer Membrane Permeabilization (MOMP) and apoptosis. Myc can also induce the expression of Bim, a pro-apoptotic member of the Bcl-2 family. Bim antagonizes anti-apoptotic proteins like Bcl-2 and Bcl-xL, tipping the balance towards apoptosis.

Ras-induced apoptosis: Ras proteins are small GTPases that transmit signals from cell surface receptors to intracellular pathways, promoting cell proliferation and survival. Oncogenic mutations in Ras are common in many cancers, leading to constitutive activation of Ras signaling. However, excessive Ras signaling can induce apoptosis through Reactive Oxygen Species (ROS) Generation and MAPK/ERK Pathway Modulation. Oncogenic Ras increases cellular ROS levels, which can cause oxidative stress and damage cellular components. High levels of ROS activate the complex apoptotic pathway by disrupting mitochondrial function. While moderate activation of the MAPK/ERK pathway promotes cell survival, excessive activation can trigger apoptosis through feedback inhibition and activation of pro-apoptotic signaling cascades.

E2F1-induced apoptosis: E2F1 is a transcription factor that controls the expression of genes involved in DNA replication and cell cycle progression. In response to oncogenic signals, E2F1 can drive cells into the S-phase of the cell cycle. However, deregulated E2F1 activity can induce apoptosis through p53 Activation and DNA Damage Response. E2F1 can increase the expression of p14ARF, leading to p53 stabilization and activation of the p53-mediated apoptotic pathway. E2F1 can induce DNA damage and activate the ATM/ATR signaling pathways, leading to the activation of pro-apoptotic factors and cell death.

Implications for cancer therapy

Understanding the oncogene-induced apoptosis has significant implications for cancer therapy. By controlling this mechanism can enhance the efficacy of treatments and overcome resistance to conventional therapies. Several strategies are being explored to control OIA in cancer treatment.

Synthetic lethality: Synthetic lethality occurs when the simultaneous disruption of two genes leads to cell death, whereas the disruption of either gene alone is non-lethal. Targeting pathways that are synthetic lethal with oncogene activation can selectively induce apoptosis in cancer cells. For example, PARP Inhibitors in BRCA1/2-mutated cancers, which are defective in homologous recombination repair, inhibition of PARP leads to synthetic lethality by accumulating DNA damage, thereby inducing apoptosis.

Targeting survival pathways: Cancer cells often activate compensatory survival pathways to prevent oncogene-induced apoptosis. Inhibiting these pathways can restore the apoptotic response. Examples include PI3K/AKT/mTOR Inhibitors, is frequently upregulated in cancer to promote cell survival. Inhibitors of PI3K, AKT, or mTOR can sensitize cancer cells to apoptosis induced by oncogenic signaling.

Epigenetic modulation: Oncogene-induced apoptosis can be influenced by the epigenetic landscape of the cell. Drugs that modulate epigenetic marks, such as DNA methylation and histone acetylation, can enhance the expression of pro-apoptotic genes. Examples include HDAC Inhibitors, increase the acetylation of histones, leading to the transcriptional activation of pro-apoptotic genes and induction of apoptosis.

Challenges and future directions

Despite the potential of exploiting oncogene-induced apoptosis for cancer therapy, several challenges remain as mentioned below.

Heterogeneity of tumor cells: The genetic and epigenetic diversity within tumors can lead to variability in the apoptotic response to oncogene activation.

Adaptive resistance: Cancer cells can develop resistance to therapies targeting OIA by activating alternative survival pathways or mutating key apoptotic regulators.

Toxicity to normal cells: Therapies that induce apoptosis in cancer cells can also affect normal cells, leading to adverse side effects.

Oncogene-induced apoptosis is a critical mechanism that can be advantageous for cancer therapy. Understanding the pathways and molecular interactions involved in OIA provides a basis for developing targeted treatments that induce cell death in cancer cells while sparing normal cells. Continued research into the mechanisms of OIA, along with the development of novel therapeutic strategies, holds potential for improving outcomes for cancer patients.