Lysosomal-Associated Protein Transmembrane-4 Beta: A Novel Potential Biomarker for Cancer Therapy with Multiple Functions
Lysosomal-associated protein transmembrane-4 beta (LAPTM4B), initially cloned from hepatocellular carcinoma (HCC), has emerged as a proto-oncogene with multifaceted roles in tumorigenesis, metastasis, therapy resistance, and cancer cell survival. Its overexpression correlates with advanced clinical stages, poor prognosis, and resistance to chemotherapy across various solid tumors, positioning it as a critical target for cancer research and therapy development.
LAPTM4B in Tumorigenesis and Progression
LAPTM4B is overexpressed in numerous malignancies, including HCC, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, and breast cancer. Clinical studies demonstrate that elevated LAPTM4B levels are associated with aggressive phenotypes, such as higher tumor grades, advanced clinical stages, and reduced overall survival (OS). For instance, in NSCLC patients, high LAPTM4B expression correlates with significantly decreased OS and poor prognoses. Similarly, in ovarian cancer, LAPTM4B overexpression drives tumor progression by enhancing cell survival, proliferation, invasion, and metastasis. Functional studies using RNA interference (RNAi) revealed that LAPTM4B knockdown in ovarian cancer cells suppresses tumorigenesis and metastasis, highlighting its direct role in cancer aggressiveness.
Mechanistically, LAPTM4B’s oncogenic activity is regulated by transcription factors and non-coding RNAs. Activator protein 4 (AP4) and cyclic adenosine monophosphate-responsive element binding protein-1 (CREB1) bind to the LAPTM4B promoter, enhancing its transcription in breast cancer and HCC. Additionally, the hepatocellular carcinoma-associated long non-coding RNA (lncRNA-HCAL) acts as a competing endogenous RNA (ceRNA) by sequestering microRNAs (miRNAs) such as miR-196b, miR-15a, and miR-196a, thereby stabilizing LAPTM4B mRNA and increasing its expression. This regulatory network underscores the complexity of LAPTM4B’s involvement in cancer biology.
Chemotherapy Resistance and Multidrug Efflux
A major clinical challenge in cancer treatment is multidrug resistance (MDR), which LAPTM4B exacerbates through multiple pathways. In ovarian cancer, LAPTM4B overexpression is linked to resistance against platinum-based chemotherapy. Similarly, LAPTM4B-35, an isoform of LAPTM4B, enhances resistance to adriamycin and epirubicin in HCC by inhibiting caspase-3 and caspase-9 activation, thereby suppressing apoptosis. This isoform also upregulates matrix metalloproteinases (MMPs), particularly MMP2 and MMP9, which contribute to extracellular matrix degradation, tumor invasion, and drug resistance.
LAPTM4B’s role in MDR extends to its interaction with the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. Overexpression of LAPTM4B-35 promotes PI3K binding, leading to AKT phosphorylation at serine 473 (p-AKT S473), a modification critical for cell survival and anti-apoptosis. Conversely, LAPTM4B knockdown reduces p-AKT levels, sensitizing cancer cells to chemotherapeutic agents. Experimental compounds like ethylglyoxal bisthiosemicarbazon (ETS) disrupt LAPTM4B expression, effectively lowering p-AKT and restoring chemosensitivity in resistant cell lines. These findings position LAPTM4B as a central mediator of MDR and a promising target for overcoming treatment resistance.
Angiogenesis and Vascular Endothelial Growth Factor Regulation
Tumor angiogenesis, essential for nutrient supply and metastasis, is another process modulated by LAPTM4B. In NSCLC and cervical cancer tissues, LAPTM4B overexpression correlates with elevated vascular endothelial growth factor (VEGF) levels, a key driver of angiogenesis. Clinical specimens from cervical intraepithelial neoplasia and cervical cancer show simultaneous upregulation of LAPTM4B-35 and VEGF, with their expression levels positively correlated. Mechanistic studies in cervical cancer cells reveal that LAPTM4B knockdown downregulates VEGF, hypoxia-inducible factor 1 alpha (HIF-1α), and MMPs, effectively impairing angiogenesis and tumor growth. These observations suggest that targeting the LAPTM4B-VEGF axis could inhibit tumor vascularization and metastasis.
Autophagy and Stress Adaptation
Autophagy, a cellular recycling process, enables cancer cells to survive metabolic stress, such as nutrient deprivation or hypoxia. LAPTM4B is localized to lysosomes and promotes autophagosome-lysosome fusion, a critical step in autophagy. Under stress conditions, LAPTM4B facilitates autophagy by interacting with Beclin1 and epidermal growth factor receptor (EGFR), as observed in nasopharyngeal carcinoma models. Serum starvation-induced autophagy is EGFR-dependent, and LAPTM4B co-localizes with EGFR in endosomes, suggesting a synergistic role in stress adaptation.
Notably, autophagy mediated by LAPTM4B supports tumor cell survival during chemotherapy and radiation. In HCC, LAPTM4B overexpression enhances autophagy under genotoxic stress, enabling cells to evade apoptosis. However, excessive autophagy can also lead to cell death, highlighting the dual role of this process in cancer. Therapeutic strategies targeting LAPTM4B-mediated autophagy may thus require careful modulation to optimize anti-tumor effects.
PI3K/AKT Signaling Pathway Activation
The PI3K/AKT pathway, a central regulator of cell survival and proliferation, is robustly activated by LAPTM4B. Overexpression of LAPTM4B-35 increases phosphorylation of AKT and its downstream targets, including Bad and glycogen synthase kinase 3 beta (GSK-3β). This activation promotes cell cycle progression, inhibits apoptosis, and enhances drug efflux. In HCC, LAPTM4B-35’s interaction with PI3K directly increases p-AKT S473 levels, fostering chemoresistance. Conversely, LAPTM4B silencing reverses these effects, underscoring its pivotal role in PI3K/AKT signaling.
LAPTM4B also intersects with the MYC proto-oncogene. By repressing MYC phosphorylation, LAPTM4B stabilizes MYC, which subsequently activates PI3K/AKT signaling and upregulates AP4, creating a feedforward loop that perpetuates oncogenic signaling. This interplay highlights LAPTM4B’s position at the nexus of multiple pro-survival pathways.
Clinical Implications and Therapeutic Potential
The consistent overexpression of LAPTM4B in diverse cancers, coupled with its roles in MDR, angiogenesis, and autophagy, positions it as a valuable biomarker and therapeutic target. Clinically, LAPTM4B levels could guide prognosis and treatment selection. For example, high LAPTM4B expression may indicate a need for therapies targeting PI3K/AKT or autophagy pathways.
Preclinical studies demonstrate the efficacy of LAPTM4B-targeted interventions. RNAi-mediated knockdown reduces tumor growth and metastasis in ovarian and prostate cancers. Similarly, the miRNA miR-188-5p suppresses LAPTM4B, inhibiting prostate cancer progression. Small molecules like ETS, which disrupt LAPTM4B-PI3K interactions, offer another therapeutic avenue by restoring chemosensitivity.
Future Directions
Despite progress, several questions remain. The precise mechanisms by which LAPTM4B regulates autophagy and interacts with EGFR require further elucidation. Additionally, the development of isoform-specific inhibitors for LAPTM4B-35 could enhance therapeutic precision. Clinical trials validating LAPTM4B as a biomarker or target are essential to translate preclinical findings into patient care.
In conclusion, LAPTM4B is a multifunctional oncoprotein driving cancer progression through diverse mechanisms. Its involvement in critical pathways like PI3K/AKT, coupled with its role in therapy resistance, underscores its potential as a biomarker and therapeutic target. Future research focusing on LAPTM4B-targeted therapies could revolutionize individualized cancer treatment.
doi:10.1097/CM9.0000000000001021
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