Matrix Metalloproteinases in Chemoresistance: Regulatory Roles, Molecular Interactions, and Potential Inhibitors

Abstract

Cancer is one of the major causes of death worldwide. Its treatments usually fail when the tumor has become malignant and metastasized. Metastasis is a key source of cancer recurrence, which often leads to resistance towards chemotherapeutic agents. Hence, most cancer-related deaths are linked to the occurrence of chemoresistance. Although chemoresistance can emerge through a multitude of mechanisms, chemoresistance and metastasis share a similar pathway, which is an epithelial-to-mesenchymal transition (EMT). Matrix metalloproteinases (MMPs), a class of zinc and calcium-chelated enzymes, are found to be key players in driving cancer migration and metastasis through EMT induction. The aim of this review is to discuss the regulatory roles and associated molecular mechanisms of specific MMPs in regulating chemoresistance, particularly EMT initiation and resistance to apoptosis. A brief presentation on their potential diagnostic and prognostic values was also deciphered. It also aimed to describe existing MMP inhibitors and the potential of utilizing other strategies to inhibit MMPs to reduce chemoresistance, such as upstream inhibition of MMP expressions and MMP-responsive nanomaterials to deliver drugs as well as epigenetic regulations. Hence, manipulation of MMP expression can be a powerful tool to aid in treating patients with chemo-resistant cancers. However, much still needs to be done to bring the solution from bench to bedside.

Figure 1

Types of cancer treatment. Different modalities evolving from conventional methods, such as surgery, chemotherapy, and radiotherapy, towards more personalized and precise therapies, including such as immunotherapy, hormonal therapy, and targeted therapy, have been used to treat various cancers. For targeted therapy, different inhibitors of MMPs have been or are testing preclinically and clinically due to their crucial roles in cancer progression and chemoresistance.

Figure 2

Structure of different types of MMPs. All MMPs are characterized by the chelated zinc in their structure, while each family can be distinguished based on other structural features such as fibronectin repeats in gelatinases and a membrane anchor in membrane type MMPs.

Figure 3

Associated mechanisms of MMPs and their effect on chemoresistance. MMP activity generally contributes to chemoresistance via EMT induction and apoptosis resistance, both of which increase cell survivability and overcome chemotherapeutic drug effects. However, several MMPs can cause chemoresistance via other pathways such as increase in pathways such as Akt, EGFR, and MAPK pathways. Other specific mechanisms such as Fas cleavage and inhibition of cell cycle arrest also contribute to chemoresistance.

Figure 4

The mechanism of action of Batimastat in cancer therapy targeting MMPs. It is suggested that inhibiting MMPs can improve chemosensitivity and reduce cancer prognosis. Abbreviation: IkBK: inhibitory-κB Kinase; NF-κB: nuclear factor-kB; JAK: Janus kinase; STAT: signal transducer and activator of transcription; RAS: rat sarcoma virus; MAPK: mitogen-activated protein kinase; AP1: activator protein 1.