Pik3c3 inhibition promotes sensitivity to colon cancer therapy by inhibiting cancer stem cells

Balawant Kumar, Rizwan Ahmad, Swagat Sharma, Saiprasad Gowrikumar, Mark Primeaux, Sandeep Rana, Amarnath Natarajan, David Oupicky, Corey R. Hopkins, Punita Dhawan, Amar B. Singh

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Background: Despite recent advances in therapies, resistance to chemotherapy remains a critical problem in the clinical management of colorectal cancer (CRC). Cancer stem cells (CSCs) play a central role in therapy resistance. Thus, elimination of CSCs is crucial for effective CRC therapy; however, such strategies are limited. Autophagy promotes resistance to cancer therapy; however, whether autophagy protects CSCs to promote resistance to CRC-therapy is not well un-derstood. Moreover, specific and potent autophagy inhibitors are warranted as clinical trials with hydroxychloroquine have not been successful. Methods: Colon cancer cells and tumoroids were used. Fluorescent reporter-based analysis of autophagy flux, spheroid and side population (SP) culture, and qPCR were done. We synthesized 36-077, a potent inhibitor of PIK3C3/VPS34 kinase, to inhibit autophagy. Combination treatments were done using 5-fluorouracil (5-FU) and 36-077. Results: The 5-FU treatment induced autophagy only in a subset of the treated colon cancer. These autophagy-enriched cells also showed increased expression of CSC markers. Co-treatment with 36-077 significantly improved efficacy of the 5-FU treatment. Mechanistic studies revealed that combination therapy inhibited GSK-3β/Wnt/β-catenin signaling to inhibit CSC population. Conclusion: Autophagy promotes resistance to CRC-therapy by specifically promoting GSK-3β/Wnt/β-catenin signaling to promote CSC survival, and 36-077, a PIK3C3/VPS34 inhibitor, helps promote efficacy of CRC therapy.

Original languageEnglish (US)
Article number2168
JournalCancers
Volume13
Issue number9
DOIs
StatePublished - May 1 2021

Keywords

  • 5-FloroUracil
  • Autophagy
  • Cancer stem cells
  • Chemoresistance
  • PI3KC3

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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