Autophagy and tumorigenesis

Park

et al. 2022

Front. Cell Dev. Biol.

The key tumor suppressor protein p53, additionally known as p53, represents an attractive target for the development and management of anti-cancer therapies. p53 has been implicated as a tumor suppressor protein that has multiple aspects of biological function comprising energy metabolism, cell cycle arrest, apoptosis, growth and differentiation, senescence, oxidative stress, angiogenesis, and cancer biology. Autophagy, a cellular self-defense system, is an evolutionarily conserved catabolic process involved in various physiological processes that maintain cellular homeostasis. Numerous studies have found that p53 modulates autophagy, although the relationship between p53 and autophagy is relatively complex and not well understood. Recently, several experimental studies have been reported that p53 can act both an inhibitor and an activator of autophagy which depend on its cellular localization as well as its mode of action. Emerging evidences have been suggested that the dual role of p53 which suppresses and stimulates autophagy in various cencer cells. It has been found that p53 suppression and activation are important to modulate autophagy for tumor promotion and cancer treatment. On the other hand, activation of autophagy by p53 has been recommended as a protective function of p53. Therefore, elucidation of the new functions of p53 and autophagy could contribute to the development of novel therapeutic approaches in cancer biology. However, the underlying molecular mechanisms of p53 and autophagy shows reciprocal functional interaction that is a major importance for cancer treatment and manegement. Additionally, several synthetic drugs and phytochemicals have been targeted to modulate p53 signaling via regulation of autophagy pathway in cancer cells. This review emphasizes the current perspectives and the role of p53 as the main regulator of autophagy-mediated novel therapeutic approaches against cancer treatment and managements.

Section: P53 Signaling Targets As a Cancer Therapy Via Modulation Of Autophagymentioning

confidence: 99%

p53 Modulation of Autophagy Signaling in Cancer Therapies: Perspectives Mechanism and Therapeutic Targets

Park

et al. 2022

Front. Cell Dev. Biol.

“…MAPK pathway inhibition alone in RAS mutant cancers has been shown to activate compensatory mechanisms and resistance to treatment; therefore, targeting both MAPK and these alternative mechanisms is a promising approach [42][43][44][45][46][47][48][49]. Autophagy, being one of these alternative mechanisms, has become an area of interest for cancer treatment [53][54][55][56][57][58][59][60]. While the relationship between the MAPK pathway and autophagy is not fully understood, there have been recent findings that the mitochondria and metabolic activity, such as AMPK-regulated activity, may be a significant connection between the two [63].…”

Section: Discussionmentioning

confidence: 99%

“…In the models of advanced as-driven cancer in which the autophagy genes are knocked out, autophagy was found to promote tumor growth [57][58][59]. The rapid proliferation of cancer cells requires high levels of energy and nutrients; moreover, autophagy is a process that cancer, a stress-inducing entity, can use to break down unnecessary components for tumor growth [60]. In fact, Ras mutant cancers have a higher level of basal autophagy than does healthy normal tissue [61].…”

Section: Autophagy As a Resistance Mechanism To Mapk Inhibitionmentioning

confidence: 99%

Clinical Translation of Combined MAPK and Autophagy Inhibition in RAS Mutant Cancer

Lee

Jain

Amaravadi

2021

IJMS

RAS (rat sarcoma virus) mutant cancers remain difficult to treat despite the advances in targeted therapy and immunotherapy. Targeted therapies against the components of mitogen-activated protein kinase (MAPK) pathways, including RAS, RAF, MEK, and ERK, have demonstrated activity in BRAF mutant and, in limited cases, RAS mutant cancer. RAS mutant cancers have been found to activate adaptive resistance mechanisms such as autophagy during MAPK inhibition. Here, we review the recent clinically relevant advances in the development of the MAPK pathway and autophagy inhibitors and focus on their application to RAS mutant cancers. We provide analysis of the preclinical rationale for combining the MAPK pathway and autophagy and highlight the most recent clinical trials that have been launched to capitalize on this potentially synthetic lethal approach to cancer therapy.

“…Thus, it is fundamental for the orderly degradation and recycling of cellular components, being instrumental for adequate cellular differentiation and survival, as well as tissue development [ 214 , 215 , 216 ]. Autophagy has a dual role in cancer, since it is important in tumour suppression in early states of the neoplastic development process, while in more advanced neoplastic states it is upregulated leading to a pro-survival and tumourigenic effect in neoplastic cells, enhanced proliferation and metastases [ 216 , 217 , 218 ]. The role of autophagy in UM development is poorly understood.…”

Section: Immunohistochemistry-based Novel Prognostic Biomarkers In Uveal Melanomamentioning

confidence: 99%

Prognostic Biomarkers in Uveal Melanoma: The Status Quo, Recent Advances and Future Directions

Lamas

Martel

Nahon-Estève

et al. 2021

Cancers

Uveal melanoma (UM) is the most common malignant intraocular tumour in the adult population. It is a rare cancer with an incidence of nearly five cases per million inhabitants per year, which develops from the uncontrolled proliferation of melanocytes in the choroid (≈90%), ciliary body (≈6%) or iris (≈4%). Patients initially present either with symptoms like blurred vision or photopsia, or without symptoms, with the tumour being detected in routine eye exams. Over the course of the disease, metastases, which are initially dormant, develop in nearly 50% of patients, preferentially in the liver. Despite decades of intensive research, the only approach proven to mildly control disease spread are early treatments directed to ablate liver metastases, such as surgical excision or chemoembolization. However, most patients have a limited life expectancy once metastases are detected, since there are limited therapeutic approaches for the metastatic disease, including immunotherapy, which unlike in cutaneous melanoma, has been mostly ineffective for UM patients. Therefore, in order to offer the best care possible to these patients, there is an urgent need to find robust models that can accurately predict the prognosis of UM, as well as therapeutic strategies that effectively block and/or limit the spread of the metastatic disease. Here, we initially summarized the current knowledge about UM by compiling the most relevant epidemiological, clinical, pathological and molecular data. Then, we revisited the most important prognostic factors currently used for the evaluation and follow-up of primary UM cases. Afterwards, we addressed emerging prognostic biomarkers in UM, by comprehensively reviewing gene signatures, immunohistochemistry-based markers and proteomic markers resulting from research studies conducted over the past three years. Finally, we discussed the current hurdles in the field and anticipated the future challenges and novel avenues of research in UM.