# Mechanisms and Function of Autophagy in Cancer

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $418,019

## Abstract

Mechanisms and Function of Autophagy in Cancer
Summary
 The overall goal of this research proposal is to elucidate the molecular mechanisms of autophagy and its
role in cancer. Autophagy is a lysosome-mediated, stress-responsive catabolic pathway that plays important
role in both normal biology and disease. Although the core molecular pathway of autophagy has been relatively
well delineated, how this pathway is precisely regulated to accomplish specific and sometime seemingly
counterintuitive function is not clear. For example, what is the mechanism that enables “autophagy-addicted”
cancer cells to possess both intact mTOR activity and high levels of basal autophagy, considering mTOR is a
bona fide inhibitor of autophagy? What is the role of autophagy in determining various cell fates such as cell
death, senescence, and stemness, which are all relevant to tumorigenesis? What therapeutic implication can
we learn from the answers to these basic biological questions concerning autophagy? In the previous funding
cycle, we have observed potent anticancer effect of autophagy-inhibition in cellular and mouse models for
multiple cancer types, including glioblastoma (GBM) and pancreatic ductal adenocarcinoma (PDAC). We
discovered that a specific protein phosphatase 2A (PP2A) complex can be stimulated to enhance autophagy
initiation through dephosphorylating the autophagy-initiating protein kinase complex, the ULK1 complex, thus
counteracting the autophagy-suppressing activity of mTOR. Importantly, our preliminary results indicate that
PP2A is also involved in the activation of TFEB transcriptional factor, a master regulator of autophagy gene
expression and lysosomal biogenesis. Therefore, via regulating the ULK1 complex and TFEB, PP2A
modulates both initiation and potency of autophagy. Intriguingly, we also found that autophagy and TFEB
regulate GBM cell senescence under clinically relevant conditions. Based on these preliminary studies, in this
grant, we will further investigate the molecular basis of autophagy and its role in cancer, by focusing on the
following two aims: (1) the mechanisms by which protein phosphatases regulate TFEB, and the functional
impact of such regulation on autophagy and autophagy-addicted cancer cells; and (2) the role of autophagy
and TFEB in cancer cell senescence. To achieve these aims, we will conduct experiments that employ a
combination of approaches, including standard cellular, molecular and biochemical approaches, animal
modeling, and more specialized technologies such as quantitative mass spectrometry and deep sequencing.
Success of the proposed study will lead to an in-depth mechanistic understanding of the regulation and
function of autophagy in normal biology and cancer biology, and might provide insights into precise targeting of
autophagy for cancer treatment. The proposal will also shed light on the functional interplay of autophagy with
other important biological processes, including lysosomal biogenesis and se...

## Key facts

- **NIH application ID:** 10371982
- **Project number:** 5R01CA166413-09
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Xuejun Jiang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $418,019
- **Award type:** 5
- **Project period:** 2013-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371982

## Citation

> US National Institutes of Health, RePORTER application 10371982, Mechanisms and Function of Autophagy in Cancer (5R01CA166413-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10371982. Licensed CC0.

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